Boronic acid derivatives and therapeutic uses thereof

ABSTRACT

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents. Other embodiments relate to pharmaceutical compositions containing boronic acid derivatives and additional excipient such as meglumine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/749,210, filed Jan. 4, 2013, and U.S. Provisional Application No.61/780,828, filed Mar. 13, 2013, the disclosures of which areincorporated herein by reference in their entireties.

BACKGROUND

Field of the Invention

The present invention relates to the fields of chemistry and medicine.More particularly, the present invention relates to boronic acidantimicrobial compounds, compositions, their preparation, and their useas therapeutic agents.

Description of the Related Art

Antibiotics have been effective tools in the treatment of infectiousdiseases during the last half-century. From the development ofantibiotic therapy to the late 1980s there was almost complete controlover bacterial infections in developed countries. However, in responseto the pressure of antibiotic usage, multiple resistance mechanisms havebecome widespread and are threatening the clinical utility ofanti-bacterial therapy. The increase in antibiotic resistant strains hasbeen particularly common in major hospitals and care centers. Theconsequences of the increase in resistant strains include highermorbidity and mortality, longer patient hospitalization, and an increasein treatment costs.

Various bacteria have evolved β-lactam deactivating enzymes, namely,β-lactamases, that counter the efficacy of the various β-lactamantibiotics. β-lactamases can be grouped into 4 classes based on theiramino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes inclasses A, C, and D include active-site serine β-lactamases, and class Benzymes, which are encountered less frequently, are Zn-dependent. Theseenzymes catalyze the chemical degradation of β-lactam antibiotics,rendering them inactive. Some β-lactamases can be transferred within andbetween various bacterial strains and species. The rapid spread ofbacterial resistance and the evolution of multi-resistant strainsseverely limits β-lactam treatment options available.

The increase of class D β-lactamase-expressing bacterium strains such asAcinetobacter baumannii has become an emerging multidrug-resistantthreat. A. baumannii strains express A, C, and D class β-lactamases. Theclass D β-lactamases such as the OXA families are particularly effectiveat destroying carbapenem type β-lactam antibiotics, e.g., imipenem, theactive carbapenems component of Merck's Primaxin® (Montefour, K.; et al.Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect.Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. AgentsChemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob.Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat tothe effective use of drugs in that category to treat and preventbacterial infections. Indeed the number of catalogued serine-basedβ-lactamases has exploded from less than ten in the 1970s to over 300variants. These issues fostered the development of five “generations” ofcephalosporins. When initially released into clinical practice,extended-spectrum cephalosporins resisted hydrolysis by the prevalentclass A β-lactamases, TEM-1 and SHV-1. However, the development ofresistant strains by the evolution of single amino acid substitutions inTEM-1 and SHV-1 resulted in the emergence of the extended-spectrumβ-lactamase (ESBL) phenotype.

New β-lactamases have recently evolved that hydrolyze the carbapenemclass of antimicrobials, including imipenem, biapenem, doripenem,meropenem, and ertapenem, as well as other β-lactam antibiotics. Thesecarbapenemases belong to molecular classes A, B, and D. Class Acarbapenemases of the KPC-type predominantly in Klebsiella pneumoniaebut now also reported in other Enterobacteriaceae, Pseudomonasaeruginosa and Acinetobacter baumannii. The KPC carbapenemase was firstdescribed in 1996 in North Carolina, but since then has disseminatedwidely in the US. It has been particularly problematic in the New YorkCity area, where several reports of spread within major hospitals andpatient morbidity have been reported. These enzymes have also beenrecently reported in France, Greece, Sweden, United Kingdom, and anoutbreak in Germany has recently been reported. Treatment of resistantstrains with carbapenems can be associated with poor outcomes.

Another mechanism of β-lactamase mediated resistance to carbapenemsinvolves combination of permeability or efflux mechanisms combined withhyper production of beta-lactamases. One example is the loss of a porincombined in hyperproduction of ampC beta-lactamase results in resistanceto imipenem in Pseudomonas aeruginosa. Efflux pump over expressioncombined with hyperproduction of the ampC β-lactamase can also result inresistance to a carbapenem such as meropenem.

Thus, there is a need for improved β-lactamase inhibitors.

SUMMARY

Some embodiments disclosed herein include a compound having thestructure of formula (I) or formula (I.1):

or pharmaceutically acceptable salt thereof, wherein:

-   -   G is selected from the group consisting of —H, —NR¹R², —CH₂N₃,        —C(O)NR′R², —CH₂C(O)NR¹R², —CH₂S(O)₂NR¹R², —CH₂—Y—Z, —CH₂—Y—X,        and —SR³;    -   Y is selected from a group consisting of —S—, —S(O)—, —S(O)₂—,        —O—, and —NR¹—;    -   R is selected from a group consisting of —H, —C₁₋₉alkyl,        —CR¹R²OC(O)C₁₋₉alkyl, —CR¹R²OC(O)OC₁₋₉alkyl, and

-   -   R¹ and R² are each independently selected from the group        consisting of —H and —C₁₋₄alkyl;    -   R³ is —C₁₋₄alkyl;    -   R⁴ is present 1 to 3 times and each R⁴ is independently selected        from the group consisting of —H, —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl,        S—C₁₋₄alkyl, —CF₃ and halogen;    -   Z is selected from the group consisting of aryl optionally        substituted with C₁₋₄alkyl, amino, hydroxy, or halogen; and        heteroaryl optionally substituted with C₁₋₄alkyl, amino,        hydroxy, or halogen;    -   X is selected from the group consisting of —C₁₋₄alkyl, —CH₂R⁵,        —CH(R⁵)₂, and —C(R⁵)₃; and    -   R⁵ is selected from the group consisting of a halogen, cyano,        and azido group.

Some embodiments disclosed herein include a compound having thestructure of formula II or formula II.1:

or pharmaceutically acceptable salt thereof, wherein G is selected fromthe group consisting of

Other embodiments disclosed herein include a pharmaceutical compositioncomprising a therapeutically effective amount of a compound disclosedherein and a pharmaceutically acceptable excipient.

Other embodiments disclosed herein include a pharmaceutical compositioncomprising a therapeutically effective amount of a compound disclosedherein and a pharmaceutically acceptable excipient.

Some embodiments disclosed herein include a pharmaceutical compositioncomprising a therapeutically effective amount of a compound disclosedherein, a pharmaceutically acceptable excipient and one or more β-lactamantibacterial agents.

Other embodiments disclosed herein include a method of treating orpreventing a bacterial infection, comprising administering to a subjectin need thereof a compound disclosed herein.

Some embodiments described herein include a pharmaceutical composition,comprising:

a monosaccharide or monosaccharide derivative; and

a compound of Formula (III):

or pharmaceutically acceptable salts thereof, wherein:

-   -   A is selected from the group consisting of C₅₋₁₀ carbocyclyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered        heterocyclyl;    -   X^(a) is —C(R^(g)R^(h))—, —O—, —S—, —S(O)—, —S(O)₂—, or —NR¹—;    -   R^(a) is selected from the group consisting of —H, halogen,        optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, optionally        substituted —S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², —CN,        optionally substituted —S(O)—C₁₋₆ alkyl, optionally substituted        —S(O)₂—C₁₋₆ alkyl, and a carboxylic acid isoster;    -   R^(b) is selected from the group consisting of —H, halogen,        optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, optionally        substituted —S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², —CN,        optionally substituted —S(O)—C₁₋₆ alkyl, optionally substituted        —S(O)₂—C₁₋₆ alkyl, and a carboxylic acid isoster, and    -   R^(c) is selected from the group consisting of —OH, optionally        substituted O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, or R^(b) and        R^(c) together with intervening atoms form a 5-8 membered boron        ester ring, optionally comprising additional 1-3 heteroatoms        selected from Oxygen (O), Sulfur(S) or Nitrogen (N);    -   R^(d) is selected from the group consisting of hydrogen, —OH,        optionally substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, or        when R^(b) and R^(c) do not together form a 5-8 membered boron        ester ring, then optionally R^(c) and R^(d) together with        intervening atoms form a 5-15 membered boron ester or amide        ring, optionally comprising additional 1-3 heteroatoms selected        from O, S, and N;    -   R^(e) is independently selected from the group consisting of        hydrogen, optionally substituted C₁₋₆alkyl, optionally        substituted C₃₋₇cycloalkyl, optionally substituted C₆₋₁₀aryl,        optionally substituted 5-10 membered heteroaryl, and optionally        substituted 3-10 membered heterocyclyl, or R^(d) and R^(e)        together with the nitrogen to which they are attached form a 5-8        membered heterocyclic ring, optionally comprising additional 1-3        heteroatoms selected from O, S or N;    -   R^(f) is independently selected from the group consisting of —H,        —OH, —C(O)G, —C(O)OG, —S(O)₂G, —C(═NR¹R²)G, —C(═NOR³)G,        optionally substituted C₁₋₆ alkyl, optionally substituted        —O—C₁₋₆alkyl, optionally substituted C₃₋₈ cycloalkyl, optionally        substituted C₆₋₁₀ aryl, optionally substituted 5-10 membered        heteroaryl, and optionally substituted 3-10 membered        heterocyclyl;    -   R^(g) and R^(h) are each independently selected from the group        consisting of —H, C₁₋₆ alkyl, —OH, —OC₁₋₆alkyl, —SC₁₋₆alkyl,        C₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —NR¹C(O)R⁵,        —NR¹S(O)₂R³, —C(O)R⁵, —C(O)OR³-alkylaryl, optionally substituted        C₆₋₁₀ aryl, optionally substituted —O—C₆₋₁₀aryl, —CN, optionally        substituted 5-10 membered heteroaryl, optionally substituted        —O-heteroaryl, optionally substituted 3-10 membered        heterocyclyl, —S(O)(R³)R⁴, —S(O)₂R³, —R¹—O—COOR³, or R^(g) and        R^(h) together with the carbon to which they are attached form a        C₃₋₈ cycloalkyl or a 4-8 membered heterocyclyl;

R is selected from the group consisting of —H, halogen, —C₁₋₉alkyl,—CR⁵R⁶OC(O)C₁₋₉alkyl, —CR⁵R⁶OC(O)OC₁₋₉alkyl, and

G is selected from the group consisting of hydrogen, —NR¹R², —CH₂N₃,—C(O)NR¹R², —CH₂C(O)NR¹R², —CH₂S(O)₂NR¹R², —(CH₂)_(n)—Y—Z,—(CH₂)_(n)—Y—X, —O—(CH₂)_(n)—C(O)NR¹R², —SR³, —CH₂NR¹C(O)R⁵,—C(═NOR³)—X, —C(═NOR³)—Z, —C(O)OR³, —C(O)—X, —C(O)—Z, —S(O)₂R³,—C(O)NR¹OR³, —NR¹(OR³), —NR¹C(O)R³, —NR¹C(O)NR²R^(1a), —NR¹C(O)OR³,—NR¹S(O)₂R³, —NR¹S(O)₂NR²R^(1a), —NR¹NR²R^(1a), —C(O)NR¹NR²R^(1a),—S(O)₂NR¹NR²R^(1a), —C(═NR¹)R⁵, —C(═NR¹)NR²R^(1a), —NR¹CR³(═NR²), and—NR¹C(═NR²)NR^(1a)R^(2a), optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 5-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl;

-   -   X is hydrogen or optionally substituted C₁₋₉alkyl;    -   Y is selected from a group consisting of —S—, —S(O)—, —S(O)₂—,        —CH₂—, —O—, —O—CH₂—, —C(O)—, and —NR¹—;    -   Z is selected from optionally substituted C₃₋₈ cycloalkyl,        optionally substituted 3-10 membered heterocyclyl, optionally        substituted C₆₋₁₀ aryl, optionally substituted 5-10 membered        heteroaryl;    -   each R¹, R², R^(1a) and R^(2a) are independently selected from        the group consisting of —H, optionally substituted —C₁₋₁₀alkyl,        optionally substituted C₂₋₁₀alkenyl, optionally substituted        C₂₋₁₀alkynyl, optionally substituted C₃₋₇ cycloalkyl, optionally        substituted 3-8 membered heterocyclyl, optionally substituted        C₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl;    -   R³ is hydrogen, optionally substituted C₁₋₁₀alkyl, —optionally        substituted C₁₋₁₀alkyl-COOH, optionally substituted C₃₋₇        cycloalkyl, optionally substituted 3-8 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, and optionally substituted        5-10 membered heteroaryl;    -   each R⁵ and R⁶ are independently selected from the group        consisting of —H, —OH, —optionally substituted alkoxyl,        optionally substituted —C₁₋₁₀alkyl, optionally substituted        C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionally        substituted C₃₋₇ cycloalkyl, optionally substituted 3-8 membered        heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionally        substituted 5-10 membered heteroaryl;    -   R⁴ is present 1 to 5 times and each R⁴ is independently selected        from the group consisting of —H, —OH, halogen, —CF₃, C₁-C₆        alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇ carbocyclyl,        5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl,        cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto),        and —(CH₂)_(m)—Y′—(CH₂)_(p)M′;    -   m and p are independently 0 to 3;    -   Y′ is selected from the group consisting of —S—, —S(O)—,        —S(O)₂—, —O—, —CR⁵R⁶—, and —NR¹—;    -   M′ is selected from the group consisting of —C(O)NR¹R²;        —C(O)NR¹OR³; —NR¹C(O)R⁵; —NR¹C(O)NR²R^(1a); —NR¹C(O)OR³;        —NR¹S(O)₂R³; —NR¹S(O)₂NR²R^(1a); —C(═NR¹)R⁵; —C(═NR¹)NR²R^(1a);        —NR¹CR⁵(═NR²); —NR¹C(═NR²)NR^(1a)R^(2a); C₁₋₄ alkyl optionally        substituted with 0-2 substituents selected from the group        consisting, —OR³, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵;        C₃₋₁₀ cycloalkyl optionally substituted with 0-2 substituents        selected from the group consisting of C₁₋₄ alkyl, —OR³, —NR¹R²,        halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; C₆₋₁₀ aryl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —OR³, —NR¹R², halogen, —C(O)NR¹R², and        —NR¹C(O)R⁵; 5 to 10 membered heteroaryl optionally substituted        with 0-2 substituents selected from the group consisting of C₁₋₄        alkyl, —OR³, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; and 4        to 10 membered heterocyclyl optionally substituted with 0-2        substituents selected from the group consisting of C₁₋₄ alkyl,        —OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; and    -   each n is independently 0-3.

Some embodiments include a chemical complex, comprising a complexbetween a monosaccharide or monosaccharide derivative and a compoundhaving the structure of formula (III) described herein.

Other embodiments disclosed herein include a method of treating orpreventing a bacterial infection, comprising administering to a subjectin need thereof a composition disclosed herein.

DETAILED DESCRIPTION

In some embodiments, compounds that contain a boronic acid moiety areprovided that act as antimicrobial agents and/or as potentiators ofantimicrobial agents. Various embodiments of these compounds includecompounds having the structures of Formulas I and II as described aboveor pharmaceutically acceptable salts thereof.

Formula I

In some embodiments, for the compounds of Formula (I), each R⁴ can beindependently selected from the group consisting of —H, —C₁₋₄alkyl, —OH,—O—C₁₋₄alkyl, and halogen; and Z can be selected from the groupconsisting of aryl optionally substituted with C₁₋₄alkyl, amino,hydroxy, or halogen and heteroaryl optionally substituted withC₁₋₄alkyl, amino, hydroxy, or halogen.

Some embodiments of compounds of Formula (I) or their pharmaceuticallyacceptable salts have the following stereochemistry as shown in thestructure of formula (Ia) or formula (Ia.1):

In some embodiments, R in any of the preceding compounds is H.

In some embodiments, R can be —CR¹R²OC(O)C₁₋₉alkyl or—CR¹R²OC(O)OC₁₋₉alkyl.

In some embodiments, R can be —CR¹R²OC(O)C₁₋₅alkyl or—CR¹R²OC(O)OC₁₋₅alkyl.

In some embodiments, R¹ in R can be H and R² in R can be H or —CH₃.

In some embodiments, R⁴ can be selected from H, F, Cl, —CH₃, —CF₃,—OCH₃, and —SCH₃.

In some embodiments, R⁴ may be either ortho, para, or meta to thecarboxylic acid moiety of the phenyl ring. In some embodiments, R⁴ inany of the preceding compounds is H.

In some embodiments, G in any of the preceding compounds is H.

In some embodiments, G can be —NR¹R². In some embodiments, G in any ofthe preceding compounds is NH₂.

In some embodiments, G can be —CH₂N₃.

In some embodiments, G in any of the preceding compounds is —C(O)NR¹R²and R¹ and R² are each independently selected from —H and C₁₋₄alkyl. Insome such embodiments, R¹ is CH₃ and R² is CH₃.

In some embodiments, G is —CH₂C(O)NR¹R² and R¹ and R² are eachindependently selected from —H and C₁₋₄alkyl. In some such embodiments,R¹ is CH₃ and R² is CH₃.

In some embodiments, G can be —CH₂S(O)₂NR¹R², and R¹ and R² are eachindependently selected from —H and C₁₋₄alkyl.

In some embodiments, R³ in any of the preceding compounds is CH₃.

In some embodiments, G is —CH₂—Y—Z; Y is —S—; and Z is selected from thegroup consisting of imidazole, N-methylimidazole, aminoimidazole,triazole, N-methyl triazole, aminotriazole, tetrazole,N-methyltetrazole, aminotetrazole, thiazole, aminothiazole, thiadiazole,aminothiadiazole, oxazole, oxadiazole, pyridine, pyridazine, pyrimidineand pyrazine, azitidine, and piperdine. In some such embodiments, Z isN-methyltetrazole. In other embodiments, Z is thiadiazole. In otherembodiments, Z is aminothiadiazole. In some embodiments, Z is azitidine.

In some embodiments, G is —CH₂—Y—X and Y is —S—. In some suchembodiments, X is —CH₃. In other embodiments, X is —CH₂CN. In otherembodiments, X is —CH₂N₃. In other embodiments, X is —CH₂F. In otherembodiments, X is —CHF₂. In some embodiments, X is —CF₃.

In some embodiments, G can be —SR³. In some embodiments, G can be SCH₃.

Some specific embodiments of the compounds described herein have thefollowing structures:

or pharmaceutically acceptable salt thereof.

Some specific embodiments of the compounds described herein have thefollowing structures:

or pharmaceutically acceptable salts thereof.

Some specific embodiments of the compounds described herein have thefollowing structures:

or pharmaceutically acceptable salts thereof.Formula II

Some embodiments include compounds having the structure of formula II asdescribed above.

In some embodiments, G is selected from the group consisting of

Some embodiments of compounds of Formula (II) or their pharmaceuticallyacceptable salts have the following stereochemistry as shown in thestructure of formula (IIa) or formula (IIa.1):

Some specific embodiments of the compounds described herein have thefollowing structures:

or pharmaceutically acceptable salt thereof.

Some specific embodiments of the compounds described herein can beselected from the following structures:

or pharmaceutically acceptable salt thereof.

Some specific embodiments of the compounds described herein can have thestructure of

or pharmaceutically acceptable salt thereof.

In some embodiments, G is selected from the group consisting of

Formula III

Some boronic acid derivatives according to Formula (III) as describedabove have a tendency to form an oligomer such as a dimer, trimer ortetramer. In some embodiments, the formation of oligomers is preventedor the amount of oligomers in a composition is reduced by including amonosaccharide or monosaccharide derivative in a composition comprisinga compound according to Formula (I), (II), or (III). Accordingly, someembodiments include a pharmaceutical composition comprising meglumineand a compound according to Formula (III) as described above.

In some embodiments, A can be selected from the group consisting ofphenyl, biphenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl,fluorenyl, indenyl, indanyl, pyridyl, pyrrolyl, oxazolyl, indolyl andthienyl.

In some embodiments of Formula (BI), R^(b) is attached to ring A at aposition that is vicinal to the point of attachment of X^(a) to ring A.

In some embodiments, R^(a) is selected from the group consisting of —H,halogen, optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionallysubstituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, optionally substituted—S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², —CN, optionally substituted—S(O)—C₁₋₆ alkyl, and optionally substituted —S(O)₂—C₁₋₆ alkyl. In someembodiments, R^(a) is a carboxylic acid isoster.

In some embodiments, R^(b) is selected from the group consisting of —H,halogen, optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionallysubstituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, optionally substituted—S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², CN, optionally substituted—S(O)—C₁₋₆ alkyl, and optionally substituted —S(O)₂—C₁₋₆ alkyl. In someembodiments, R^(b) is a carboxylic acid isoster.

The compound of formula (III) can have the structure of Formula (IIIa):

-   -   or pharmaceutically acceptable salts thereof, wherein J, L, and        M are independently selected from the group consisting of CR⁴        and N.

In some embodiments, R^(b) can be —OH or optionally substituted—OC₁₋₆alkyl. In some embodiments, R^(c) can be —OH or optionallysubstituted —OC₁₋₆alkyl. In some embodiments, R^(b) can be —OH. In someembodiments, R^(c) can be —OH. In some embodiments, R^(b) can be —OH andR^(c) can be —OH.

In some embodiments, R^(b) and R^(c) together with intervening atomsform a 5-8 membered boron ester ring, optionally comprising additional1-3 heteroatoms selected from Oxygen (O), Sulfur(S) or Nitrogen (N).

The compounds of Formula (III) or their pharmaceutically acceptablesalts can also have the structure of formula (IIIb):

or pharmaceutically acceptable salts thereof, wherein J, L, and M areindependently selected from the group consisting of CR⁴ and N.

Some embodiments of compounds of Formula (IIIb) or theirpharmaceutically acceptable salts have the following stereochemistry asshown in the structure of formula (IIIc):

or pharmaceutically acceptable salts thereof.

In some embodiments, R^(a) can be C(O)OR and R can be—CR⁵R⁶OC(O)C₁₋₉alkyl or —CR⁵R⁶OC(O)OC₁₋₉alkyl. In some embodiments,R^(a) can be C(O)OH.

In some embodiments, R can be —OCH₂OC(O)—C(CH₃)₃, —OCH₂OC(O)—CH(CH₃)₂,or —OCH₂OC(O)—(CH₂)_(n)CH₃. In some embodiments, R can be—CH₂OC(O)OCH(CH₃)₂. In some embodiments, R can be —CH₂OC(O)OC(CH₃)₃. Insome embodiments, R can be —CH₂OC(O)OC(CH₂)₂CH₃. In some embodiments, Rcan be —CH₂OC(O)OCH(CH₂CH₃)₂. In some embodiments, R can be—CH₂C(O)OCH₂CH₃. In some embodiments, R can be

In some embodiments, R^(d) can be selected from hydrogen, —OH, halogen,—COOR, optionally substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹. Insome embodiments, R^(d) can be —OH or optionally substituted —O—C₁₋₆alkyl. In some embodiments, R^(d) can be —OH.

In some embodiments, R^(e) can be independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆alkyl, optionallysubstituted C₃₋₇cycloalkyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, and optionally substituted 3-10membered heterocyclyl.

In some embodiments, R^(f) can be independently selected from the groupconsisting of —C(O)G, —C(O)OG, and —S(O)₂G. In some embodiments, R^(f)can be independently selected from —C(O)G or —C(O)OG.

In some embodiments, G can be selected from the group consisting of

In some embodiments, G is —NH₂. In some embodiments, G can be—NH—C₁₋₄alkyl. In some embodiments, G is —C(O)NR¹R² and R¹ and R² in Gcan be each independently selected from —H and C₁₋₄alkyl. In someembodiments, G can be —CH₂C(O)NR¹R² and R¹ and R² in G are eachindependently selected from —H and C₁₋₄alkyl.

In some embodiments, G is —O—(CH₂)_(n)—C(O)NR₁R₂; n in G is 0-3; and R¹and R² in G are each independently selected from —H and C₁₋₄alkyl. Insome embodiments, G is —O—CH₂—C(O)NH₂.

In some embodiments, G is —(CH₂)_(n)—Y—Z; n in G is 0-3, Y is —S—; and Zis selected from the group consisting of imidazole, N-methylimidazole,aminoimidazole, triazole, N-methyl triazole, aminotriazole, tetrazole,N-methyltetrazole, aminotetrazole, thiazole, aminothiazole, thiadiazole,aminothiadiazole, oxazole, oxadiazole, pyridine, pyridazine, pyrimidine,pyrazine, azetidine and piperdine, each optionally substituted with oneor more C₁₋₄alkyl, —NR¹R², hydroxy, or halogen. In some embodiments, nin G is 0. In some embodiments, n in G is 1.

In some embodiments, Z can be thiadiazole optionally substituted withone or more C₁₋₄alkyl, —NR¹R², hydroxy, or halogen.

In some embodiments, Z can be aminothiadiazole optionally substitutedwith one or more C₁₋₄alkyl, —NR¹R², hydroxy, or halogen.

In some embodiments, Z can be azitidine optionally substituted with oneor more C₁₋₄alkyl, —NR¹R², hydroxy, or halogen.

In some embodiments, G is —(CH₂)_(n)—Y—X; n in G is 0-3; Y is —S—; and Xis hydrogen or optionally C₁₋₄alkyl. In some embodiments, n in G is 0.In some embodiments, n in G is 1. In some embodiments, X is —CH₃. Insome embodiments, X is —CH₂CN. In some embodiments, X is —CH₂N₃. In someembodiments, X is —CH₂F. In some embodiments, X is —CHF₂. In someembodiments, X is —CF₃.

In some embodiments, G can be —(CH₂)_(n)—Y—Z; n in G can be 0-3, Y canbe —CH₂—, —O—, —O—CH₂—, —C(O)—; and Z can be selected from the groupconsisting of phenyl, napthal, indole, pyrrolidine, thiophene,cyclopropyl, or cyclohexyl, each optionally substituted with one or moreC₁₋₄alkyl, —NR¹R², hydroxy, or halogen. In some embodiments, n in Gis 1. In some embodiments, n in G is 2. In some embodiments, Z isselected from

In some embodiments, G is —(CH₂)_(n)—Y—X; n in G is 0-3; Y is —O— or—CH—; and X is C₁₋₄alkyl optionally substituted with one or morehalogen, cyano, or azido. In some embodiments, n in G is 0 and Y is —O—.In some embodiments, n in G is 1. In some embodiments, n in G is 2. Insome embodiments, X is optionally substituted C₁₋₄alkyl.

In some embodiments, X^(a) can be —CH2—. In some embodiments, X^(a) canbe —O—. In some embodiments, X^(a) can be —S—. In some embodiments,X^(a) can be —NH—.

In some embodiments, R^(g) can be H and R^(h) can be H.

Some specific examples of the compound of formula (III) include

or pharmaceutically acceptable salts thereof.

Other specific examples of the compound of formula (III) include

or pharmaceutically acceptable salts thereof.

Some embodiments of any of the compounds described above includeprodrugs (e.g., prodrug esters), metabolites, stereoisomers, hydrates,solvates, polymorphs, and pharmaceutically acceptable salts of thosecompounds.

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

In some embodiments, due to the facile exchange of boron esters, thecompounds described herein may convert to or exist in equilibrium withalternate forms. Accordingly, in some embodiments, the compoundsdescribed herein may exist in combination with one or more of theseforms. For example, as shown below, the compounds disclosed herein mayexist in cyclic form as cyclic boronate monoesters as formula I (or II)or in acyclic form as boronic acids as formula I.1 (or II.1)(Biochemistry, 2000, 39, 5312-21), or may exist as a mixture of the twoforms depending on the medium.

In some embodiments, the compounds described herein may exist in cyclicdimeric form as Formula (C) or trimeric form as Formula (D), tetramericform as Formula (E) as shown below, or acylic dimeric, trimeric ortetrameric forms and the like. In some embodiments, X′ can be—NR^(e)R^(f) in Formula C, D and E. In some embodiments, X′ can be—NHC(O)—G in Formula C, D and E.

DEFINITIONS

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, (ed. H.Bundgaard, Elsevier, 1985), which is hereby incorporated herein byreference in its entirety.

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include pivoyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of pro-drug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A. C. S. Symposium Series, American Chemical Society (1975); and“Bioreversible Carriers in Drug Design: Theory and Application”, editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providingexamples of esters useful as prodrugs for compounds containing carboxylgroups). Each of the above-mentioned references is herein incorporatedby reference in their entirety.

“Metabolites” of the compounds disclosed herein include active speciesthat are produced upon introduction of the compounds into the biologicalmilieu.

“Solvate” refers to the compound formed by the interaction of a solventand a compound described herein, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of a compound, which are notbiologically or otherwise undesirable for use in a pharmaceutical. Inmany cases, the compounds herein are capable of forming acid and/or basesalts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. Many such salts areknown in the art, as described in WO 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein in itsentirety).

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.

The term “halogen” or “halo,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorinebeing preferred.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that is fully saturated (i.e., contains no double or triplebonds). The alkyl group may have 1 to 20 carbon atoms (whenever itappears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 9 carbon atoms. The alkyl group could also be alower alkyl having 1 to 4 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁₋₄ alkyl” or similar designations. By way ofexample only, “C₁₋₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from thegroup consisting of methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but arein no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, pentyl, hexyl, and the like.

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkylas is defined above, such as “C₁₋₉ alkoxy”, including but not limited tomethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, “alkylthio” refers to the formula —SR wherein R is analkyl as is defined above, such as “C₁₋₉ alkylthio” and the like,including but not limited to methylmercapto, ethylmercapto,n-propylmercapto, 1-methylethylmercapto (isopropylmercapto),n-butylmercapto, iso-butylmercapto, sec-butylmercapto,tert-butylmercapto, and the like.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkenyl” where no numerical range is designated.The alkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group of the compounds may be designated as“C₂₋₄ alkenyl” or similar designations. By way of example only, “C₂₋₄alkenyl” indicates that there are two to four carbon atoms in thealkenyl chain, i.e., the alkenyl chain is selected from the groupconsisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl,buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl,2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl,buta-1,3-dienyl, buta-1,2, -dienyl, and buta-1,2-dien-4-yl. Typicalalkenyl groups include, but are in no way limited to, ethenyl, propenyl,butenyl, pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.The alkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group of the compounds may be designated as“C₂₋₄ alkynyl” or similar designations. By way of example only, “C₂₋₄alkynyl” indicates that there are two to four carbon atoms in thealkynyl chain, i.e., the alkynyl chain is selected from the groupconsisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl,butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in noway limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, andthe like.

As used herein, “heteroalkyl” refers to a straight or branchedhydrocarbon chain containing one or more heteroatoms, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen and sulfur, in the chain backbone. The heteroalkyl group may have1 to 20 carbon atoms although the present definition also covers theoccurrence of the term “heteroalkyl” where no numerical range isdesignated. The heteroalkyl group may also be a medium size heteroalkylhaving 1 to 9 carbon atoms. The heteroalkyl group could also be a lowerheteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of thecompounds may be designated as “C₁₋₄ heteroalkyl” or similardesignations. The heteroalkyl group may contain one or more heteroatoms.By way of example only, “C₁₋₄ heteroalkyl” indicates that there are oneto four carbon atoms in the heteroalkyl chain and additionally one ormore heteroatoms in the backbone of the chain.

The term “aromatic” refers to a ring or ring system having a conjugatedpi electron system and includes both carbocyclic aromatic (e.g., phenyl)and heterocyclic aromatic groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of atoms) groups provided that the entire ring system is aromatic.

As used herein, “aryl” refers to an aromatic ring or ring system (i.e.,two or more fused rings that share two adjacent carbon atoms) containingonly carbon in the ring backbone. When the aryl is a ring system, everyring in the system is aromatic. The aryl group may have 6 to 18 carbonatoms, although the present definition also covers the occurrence of theterm “aryl” where no numerical range is designated. In some embodiments,the aryl group has 6 to 10 carbon atoms. The aryl group may bedesignated as “C₆₋₁₀ aryl,” “C₆ or C₁₀ aryl,” or similar designations.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, azulenyl, and anthracenyl.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl as is defined above, such as “C₆₋₁₀ aryloxy” or “C₆₋₁₀arylthio” and the like, including but not limited to phenyloxy.

An “aralkyl” or “arylalkyl” is an aryl group connected, as asubstituent, via an alkylene group, such “C₇₋₁₄ aralkyl” and the like,including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, andnaphthylalkyl. In some cases, the alkylene group is a lower alkylenegroup (i.e., a C₁₋₄ alkylene group).

As used herein, “heteroaryl” refers to an aromatic ring or ring system(i.e., two or more fused rings that share two adjacent atoms) thatcontain(s) one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen and sulfur, inthe ring backbone. When the heteroaryl is a ring system, every ring inthe system is aromatic. The heteroaryl group may have 5-18 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heteroaryl” where no numerical range isdesignated. In some embodiments, the heteroaryl group has 5 to 10 ringmembers or 5 to 7 ring members. The heteroaryl group may be designatedas “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similardesignations. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,indolyl, isoindolyl, and benzothienyl.

A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, asa substituent, via an alkylene group. Examples include but are notlimited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. Insome cases, the alkylene group is a lower alkylene group (i.e., a C₁₋₄alkylene group).

As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ringsystem containing only carbon atoms in the ring system backbone. Whenthe carbocyclyl is a ring system, two or more rings may be joinedtogether in a fused, bridged or spiro-connected fashion. Carbocyclylsmay have any degree of saturation provided that at least one ring in aring system is not aromatic. Thus, carbocyclyls include cycloalkyls,cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20carbon atoms, although the present definition also covers the occurrenceof the term “carbocyclyl” where no numerical range is designated. Thecarbocyclyl group may also be a medium size carbocyclyl having 3 to 10carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3to 6 carbon atoms. The carbocyclyl group may be designated as “C₃₋₆carbocyclyl” or similar designations. Examples of carbocyclyl ringsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl,adamantyl, and spiro[4.4]nonanyl.

A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as asubstituent, via an alkylene group, such as “C₄₋₁₀ (carbocyclyl)alkyl”and the like, including but not limited to, cyclopropylmethyl,cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl,cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. Insome cases, the alkylene group is a lower alkylene group.

As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring orring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, “cycloalkenyl” means a carbocyclyl ring or ring systemhaving at least one double bond, wherein no ring in the ring system isaromatic. An example is cyclohexenyl.

As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ringsystem containing at least one heteroatom in the ring backbone.Heterocyclyls may be joined together in a fused, bridged orspiro-connected fashion. Heterocyclyls may have any degree of saturationprovided that at least one ring in the ring system is not aromatic. Theheteroatom(s) may be present in either a non-aromatic or aromatic ringin the ring system. The heterocyclyl group may have 3 to 20 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heterocyclyl” where no numerical range isdesignated. The heterocyclyl group may also be a medium sizeheterocyclyl having 3 to 10 ring members. The heterocyclyl group couldalso be a heterocyclyl having 3 to 6 ring members. The heterocyclylgroup may be designated as “3-6 membered heterocyclyl” or similardesignations. In preferred six membered monocyclic heterocyclyls, theheteroatom(s) are selected from one up to three of O, N or S, and inpreferred five membered monocyclic heterocyclyls, the heteroatom(s) areselected from one or two heteroatoms selected from 0, N, or S. Examplesof heterocyclyl rings include, but are not limited to, azepinyl,acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl,imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl,1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl,1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl,isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl,thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, andtetrahydroquinoline.

A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as asubstituent, via an alkylene group. Examples include, but are notlimited to, imidazolinylmethyl and indolinylethyl.

As used herein, “acyl” refers to —C(═O)R, wherein R is hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein. A non-limiting example includes carboxyl (i.e.,—C(═O)OH).

A “cyano” group refers to a “—CN” group.

A “cyanato” group refers to an “—OCN” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—SCN” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “sulfonyl” group refers to an “—SO₂R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

An “S-sulfonamido” group refers to a “—SO₂NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-sulfonamido” group refers to a “—N(R_(A))SO₂R_(B)” group in whichR_(A) and R_(b) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-carbamyl” group refers to a “—OC(═O)NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-carbamyl” group refers to an “—N(R_(A))OC(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-thiocarbamyl” group refers to a “—OC(═S)NR_(A)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, aC₆₋₁₀ ryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

An “N-thiocarbamyl” group refers to an “—N(R_(A))OC(═S)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

A “C-amido” group refers to a “—C(═O)NR_(A)R_(B)” group in which R_(A)and R_(B) are each independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-amido” group refers to a “—N(R_(A))C(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “amino” group refers to a “—NR_(A)R_(B)” group in which R_(A) andR_(B) are each independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “aminoalkyl” group refers to an amino group connected via an alkylenegroup.

An “alkoxyalkyl” group refers to an alkoxy group connected via analkylene group, such as a “C₂₋₈ alkoxyalkyl” and the like.

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substitutents independently selected fromC₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy,sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., —CF), halo(C₁-C₆)alkoxy(e.g., —OCF₃), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl,nitro, O-carbamyl, N-carbamyl, 0-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, 0-carboxy, acyl,cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl,and oxo (═O). Wherever a group is described as “optionally substituted”that group can be substituted with the above substituents.

In some embodiments, substituted group(s) is (are) substituted with oneor more substituent(s) individually and independently selected fromC₁-C₄ alkyl, amino, hydroxy, and halogen.

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂—, —CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene” or“alkenylene.”

As used herein, “alkylene” means a branched, or straight chain fullysaturated di-radical chemical group containing only carbon andhydrogenthat is attached to the rest of the molecule via two points ofattachment (i.e., an alkanediyl). The alkylene group may have 1 to 20carbon atoms, although the present definition also covers the occurrenceof the term alkylene where no numerical range is designated. Thealkylene group may also be a medium size alkylene having 1 to 9 carbonatoms. The alkylene group could also be a lower alkylene having 1 to 4carbon atoms. The alkylene group may be designated as “C₁₋₄ alkylene” orsimilar designations. By way of example only, “C₁₋₄ alkylene” indicatesthat there are one to four carbon atoms in the alkylene chain, i.e., thealkylene chain is selected from the group consisting of methylene,ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl,1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene,1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

As used herein, “alkenylene” means a straight or branched chaindi-radical chemical group containing only carbon and hydrogen andcontaining at least one carbon-carbon double bond that is attached tothe rest of the molecule via two points of attachment. The alkenylenegroup may have 2 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term alkenylene where no numericalrange is designated. The alkenylene group may also be a medium sizealkenylene having 2 to 9 carbon atoms. The alkenylene group could alsobe a lower alkenylene having 2 to 4 carbon atoms. The alkenylene groupmay be designated as “C₂₋₄ alkenylene” or similar designations. By wayof example only, “C₂₋₄ alkenylene” indicates that there are two to fourcarbon atoms in the alkenylene chain, i.e., the alkenylene chain isselected from the group consisting of ethenylene, ethen-1,1-diyl,propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene,but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl,but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl,1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl,1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene,2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl,and 2,2-dimethyl-ethen-1,1-diyl.

The term “agent” or “test agent” includes any substance, molecule,element, compound, entity, or a combination thereof. It includes, but isnot limited to, e.g., protein, polypeptide, peptide or mimetic, smallorganic molecule, polysaccharide, polynucleotide, and the like. It canbe a natural product, a synthetic compound, or a chemical compound, or acombination of two or more substances. Unless otherwise specified, theterms “agent”, “substance”, and “compound” are used interchangeablyherein.

The term “analog” is used herein to refer to a molecule thatstructurally resembles a reference molecule but which has been modifiedin a targeted and controlled manner, by replacing a specific substituentof the reference molecule with an alternate substituent. Compared to thereference molecule, an analog would be expected, by one skilled in theart, to exhibit the same, similar, or improved utility. Synthesis andscreening of analogs, to identify variants of known compounds havingimproved characteristics (such as higher binding affinity for a targetmolecule) is an approach that is well known in pharmaceutical chemistry.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes, but is not limited to, primates, includingsimians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep,goats, swine, rabbits, dogs, cats, rats and mice but also includes manyother species.

The term “microbial infection” refers to the invasion of the hostorganism, whether the organism is a vertebrate, invertebrate, fish,plant, bird, or mammal, by pathogenic microbes. This includes theexcessive growth of microbes that are normally present in or on the bodyof a mammal or other organism. More generally, a microbial infection canbe any situation in which the presence of a microbial population(s) isdamaging to a host mammal. Thus, a mammal is “suffering” from amicrobial infection when excessive numbers of a microbial population arepresent in or on a mammal's body, or when the effects of the presence ofa microbial population(s) is damaging the cells or other tissue of amammal. Specifically, this description applies to a bacterial infection.Note that the compounds of preferred embodiments are also useful intreating microbial growth or contamination of cell cultures or othermedia, or inanimate surfaces or objects, and nothing herein should limitthe preferred embodiments only to treatment of higher organisms, exceptwhen explicitly so specified in the claims.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. In addition, various adjuvants such as are commonly usedin the art may be included. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 8th Ed., Pergamon Press, which is incorporated herein byreference in its entirety. The pharmaceutically acceptable excipient canbe a monosaccharide or monosaccharide derivative.

“Subject” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

An “effective amount” or a “therapeutically effective amount” as usedherein refers to an amount of a therapeutic agent that is effective torelieve, to some extent, or to reduce the likelihood of onset of, one ormore of the symptoms of a disease or condition, and includes curing adisease or condition. “Curing” means that the symptoms of a disease orcondition are eliminated; however, certain long-term or permanenteffects may exist even after a cure is obtained (such as extensivetissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a pharmaceutical composition for prophylactic and/ortherapeutic purposes. The term “prophylactic treatment” refers totreating a subject who does not yet exhibit symptoms of a disease orcondition, but who is susceptible to, or otherwise at risk of, aparticular disease or condition, whereby the treatment reduces thelikelihood that the patient will develop the disease or condition. Theterm “therapeutic treatment” refers to administering treatment to asubject already suffering from a disease or condition.

“Monosaccharide” as used herein refers to a chemical compound of generalformula C_(x)(H₂O)_(x), where x is 3 to 10. Examples of monosaccharideinclude but are not limited to glucose (dextrose), arabinose, mannitol,fructose (levulose) and galactose. “Monosaccharide derivative” as usedherein refers to a monosaccharide wherein one or more —OH groups can bereplaced by the substituents described above in the definition of“substituted.” In some monosaccharide derivatives, one or more —OHgroups on the monosaccharide can be replaced by one or more —NH₂ or—NH—CH₃ groups. One example of a monosaccharide derivative includesmeglumine. Other examples of a monosaccharide derivative can include anamino alcohol.

As used herein, “isosteres” are different compounds that have differentmolecular formulas but exhibit the same or similar properties. Forexample, tetrazole is an isostere of carboxylic acid because it mimicsthe properties of carboxylic acid even though they both have verydifferent molecular formulae. Tetrazole is one of many possibleisosteric replacements for carboxylic acid. Other carboxylic acidisosteres contemplated include —COOH, —SO₃H, —SO₂HNR⁹, —PO₂(R⁹)₂,—PO₃(R⁹)₂, —CONHNHSO₂R⁹, —COHNSO₂R⁹, and —CONR⁹CN. In addition,carboxylic acid isosteres can include 5-7 membered carbocycles orheterocycles containing any combination of CH₂, O, S, or N in anychemically stable oxidation state, where any of the atoms of said ringstructure are optionally substituted in one or more positions. Thefollowing structures are non-limiting examples of carbocyclic andheterocyclic isosteres contemplated. The atoms of said ring structuremay be optionally substituted at one or more positions with R⁹.

It is also contemplated that when chemical substituents are added to acarboxylic isostere, the compound retains the properties of a carboxylicisostere. It is contemplated that when a carboxylic isostere isoptionally substituted with one or more moieties selected from R⁹, thenthe substitution cannot eliminate the carboxylic acid isostericproperties of the compound. It is also contemplated that the placementof one or more R⁹ substituents upon a carbocyclic or heterocycliccarboxylic acid isostere shall not be permitted at one or more atom(s)which maintain(s) or is/are integral to the carboxylic acid isostericproperties of the compound, if such substituent(s) would destroy thecarboxylic acid isosteric properties of the compound. Other carboxylicacid isosteres not specifically exemplified or described in thisspecification are also contemplated.

Methods of Preparation

The compounds disclosed herein may be synthesized by methods describedbelow, or by modification of these methods. Ways of modifying themethodology include, among others, temperature, solvent, reagents etc.,known to those skilled in the art. In general, during any of theprocesses for preparation of the compounds disclosed herein, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973);and P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis(3rd ed.) Wiley, New York (1999), which are both hereby incorporatedherein by reference in their entirety. The protecting groups may beremoved at a convenient subsequent stage using methods known from theart. Synthetic chemistry transformations useful in synthesizingapplicable compounds are known in the art and include e.g. thosedescribed in R. Larock, Comprehensive Organic Transformations, VCHPublishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons, 1995, which are both herebyincorporated herein by reference in their entirety. The routes shown anddescribed herein are illustrative only and are not intended, nor arethey to be construed, to limit the scope of the claims in any mannerwhatsoever. Those skilled in the art will be able to recognizemodifications of the disclosed syntheses and to devise alternate routesbased on the disclosures herein; all such modifications and alternateroutes are within the scope of the claims.

In the following schemes, protecting groups for oxygen atoms areselected for their compatibility with the requisite synthetic steps aswell as compatibility of the introduction and deprotection steps withthe overall synthetic schemes (P. G. M. Green, T. W. Wutts, ProtectingGroups in Organic Synthesis (3rd ed.) Wiley, New York (1999)). Handlingof protecting and/or sterodirecting groups specific to boronic acidderivatives is described in a recent review of chemistry of boronicacids: D. G. Hall (Ed.), Boronic Acids. Preparation and Application inOrganic Synthesis and Medicine, Wiley VCH (2005) and in earlier reviews:Matteson, D. S. (1988). Asymmetric synthesis with boronic esters.Accounts of Chemical Research, 21(8), 294-300, and Matteson, D. S.(1989). Tetrahedron, 45(7), 1859-1885), all of which are incorporatedherein by reference in their entirety. The latter review articles alsodescribe methodology for stereoselective insertion of halomethinefunctionality next to the boronate which is employed in the syntheticschemes below.

In addition to standard acid catalyzed deprotection, special methods forremoval of boronic acid protecting and/or sterodirecting groups methodsusing fluorides (Yuen, A. K. L., & Hutton, C. A. (2005). TetrahedronLetters, 46(46), 7899-7903—incorporated herein by reference in itsentirety) or periodate oxidation (Coutts, S. J., et al. (1994).Tetrahedron Letters, 35(29), 5109-5112—incorporated herein by referencein its entirety) can also be employed in preparations of the compoundsdisclosed herein.

In strategies employing pinanediol or other diol-based chiralauxiliaries for stereospecific introduction of new chiral centers, theearly stages of chemistry on boronic intermediates can be performed onchiral boronate esters or alternatively nonchiral borate/boronateintermediates can be used in early stages followed bytransesterification with chiral diols prior to the step wherestereoselection is required.

Synthesis of Compounds of Formula I

Compounds of formula I (for example, compounds of formula Ia) where R isH can be prepared as depicted in scheme 1 from intermediates of formulaIa-2, which may be assembled by several known α-aminoboronate formationreactions (Boronic Acids: Preparations and Applications in OrganicSynthesis, Medicine and Materials, D. G. Hall, ed., Wiley-VCH, Weinheim,2011, which is incorporated herein by reference in its entirety).

Such intermediates of formula Ia-2 where X=—N(TMS)₂ and R′ and R″ arealkyl groups may be prepared by earlier described methods (PCTPublication Nos. WO09064414 and WO10130708, which are incorporatedherein by reference in their entirety). In an alternate sequence,compounds of formula Ia-2, where X=—N(TMS)₂ and R″ is Boc and R′ ist-Butyl or R′ and R″ are protected together as isopropylidene or anyother groups protected separately or together in cyclic form, may bemade from compounds of formula Ia-3 via homologation to givechloromethylene addition product with good stereocontrol by Mattesonreaction conditions, followed by stereospecific substitution withhexamethyldisilazane (PCT Publication No. WO0946098, which isincorporated herein by reference in its entirety). Bromo precursors maybe made analogously to the chloro compounds utilizing dibromomethane (J.Am. Chem. Soc. 1990, 112, 3964-969, which is incorporated herein byreference in its entirety). Matteson reaction precursors of formula Ia-3may be made by palladium mediated coupling of pinanediol diboronate fromcorresponding appropriately protected benzyl alcohols (J. Am. Chem. Soc.2011, 133, 409-411, which is incorporated herein by reference in itsentirety) or benzyl bromides Ia-4 (Tetrahedron Letters 2003, 44,233-235; J. Am. Chem. Soc., 2010, 132, 11825-11827, which isincorporated herein by reference in its entirety). Compounds of formulaIa-3 may also be prepared by homologation of the correspondingarylboronate ester by reaction with chloromethyl anion (PCT PublicationNo. WO09064414, which is incorporated herein by reference in itsentirety). The compounds of formula Ia-4 may be achieved by means ofseveral earlier known methods (PCT Publication No. WO0458679, which isincorporated herein by reference in its entirety) with conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry (ed. J. F. W. McOmie, Plenum, 1973); and ProtectingGroups in Organic Synthesis, P. G. M. Wutts, T. W. Green, Wiley, NewYork, 1999) (both incorporated herein by reference in their entirety)from commercially available salicylic acid derivatives. Compounds offormula Ia-4 where Y is methyl can be readily transformed tocorresponding benzyl bromides (Bioorg. Med. Chem. Lett. 1999, 9, 34-346,which is incorporated herein by reference in its entirety) forboronation reaction to give Ia-3.

Bis-trimethyl silylamides of formula Ia-2 may be reacted in situ with anacid chloride to result directly in analogs of formula Ia-1. Suchanalogs of Ia-1 can also be made via coupling of the bis-TMS amine withcommercially available carboxylic acids under typical amide couplingconditions (e.g., carbodiimide or HATU coupling) (Tetrahedron, 2005, 61,10827-10852, which is incorporated herein by reference in its entirety).Varieties of substituted thioacetic acid or glycolate or glycinateprecursors are commercially available. Such precursors may be alsoobtained by several well-known methods in the literature (J. Org. Chem.(2012), DOI: 10.1021/jo302088t, which is incorporated herein byreference in its entirety).

Simultaneous deprotection of pinane ester and salicylic acid protectivegroups of compounds of formula Ia-1 can be achieved by heating withdilute HCl, affording the desired compounds of formula Ia. Thistransformation may also be achieved by treatment with BCl₃ or BBr₃ (PCTPublication No. WO09064414, which is incorporated herein by reference inits entirety). Alternatively, the deprotection may be attained viatrans-esterification with isobutyl boronic acid in presence of diluteacid (PCT Publication No. WO09064413, which is incorporated herein byreference in its entirety) or via other known methods (J. Org. Chem.(2010), 75, 468-471, which is incorporated herein by reference in itsentirety).

In an alternate approach, compounds of formula Ia-2 where X is NH₂.HClcan be made via asymmetric addition of boron to a carbon heteroatomdouble bond, enabling production of enantiomerically pureN-sulfinyl-α-amino boronate ester derivatives. Such transformation isachieved form appropriately protected N-sulfinyl imine (Ia-5) using aCu/ligand catalyst system (J. Am. Chem. Soc. (2008), 130, 6910-6911,which is incorporated herein by reference in its entirety) followed bytreatment with mild acid. Enantiomerically pure N-sulfinyl imines offormula Ia-5 may be made by condensation of appropriately protectedphenylacetaldehyde intermediates (Ia-6) and enantiomerically puret-butylsulfonylamine (Chem. Rev. 2010, 110, 3600-3740, which isincorporated herein by reference in its entirety).

Phenylacetaldehyde derivatives of formula Ia-6 can be made from Claisenrearrangement of allyl ethers of commercially available salicylatesfollowed by oxidative cleavage of the allyl group (J. Med. Chem. 1995,38, 3094-3105, which is incorporated herein by reference in itsentirety). Such intermediates of formula Ia-6 can also be made by Wackeroxidation of vinyl substituted salicylates (Org. Lett. 2012, 14,3237-3239, which is incorporated herein by reference in its entirety).Protective groups may be used separately for phenol and acid or togetherfrom a variety of available options as described above.

One exemplary but non-limiting general synthetic scheme for preparingcompound of Formula Ia is shown below in Scheme 1a. For the startingcompound of Formula I-1, Y can be —OH, halogen, —C₁₋₁₀ alkyl, —C₁₋₁₀alkyl-OH, —C₁₋₁₀ alkyl-halogen, R^(1A) can be hydrogen or C₁₋₁₀ alkyl,and R^(2A) can be hydrogen or C₁₋₁₀ alkyl. The compound of Formula I-1can be treated first with TFA and TFAA and then withBis(pinacolato)diboron to form a pinacol boronic ester compound ofFormula I-3. The compound of Formula I-3 is then reacted with pinanediolto yield a Pinanediol Methylboronic Ester Compound of Formula I-4. Thecompound of Formula I-4 undergoes homologation to yield a compound ofFormula I-5, which then undergoes another homologation reaction toprovide a chloroethlene product of Formula I-6. The compound of FormulaI-6 reacts with the bis-TMS amine to form a bis-trimethyl silyamine ofFormula I-7. Different types of thioacetic acid, glycolate or glycinateprecursors can then react with the compound of Formula I-7 to form anamide of Formula I-8. The compound of Formula I-8 then undergoes thedeprotection of the pinane ester and salicylic acid protective groups toafford the compound of Formula Ia.

Alternatively, compounds of Formula Ia can also be prepared by using thegeneral synthetic Scheme 1b illustrated below. The starting compound ofFormula I-2 can be prepared by adding protective groups to a salicylatederivative compound following procedures described above in Scheme 1a.The compound of Formula I-2 can be treated with vinyl trifluoroborate toform a vinyl phenyl compound of Formula I-9. The compound of Formula I-9then undergoes reaction to form a phneylacetaldehyde derivative ofFormula I-10. The compound of Formula I-10 then reacts with(R)-t-butylsulfinic amide to provide a N-sulfinyl imine compound ofFormula I-11. The compound of Formula I-11 undergoes boron addition toform a pinacol boronic ester compound of Formula I-12. The compound ofFormula I-12 can react with the acid to remove the t-butylsulfinicgroup. Different types of thioacetic acid, glycolate or glycinateprecursors can then react with the compound of Formula I-13 to form anamide of Formula I-14. The amide of Formula I-14 can react withpinanediol to yield a Pinanediol Methylboronic Ester Compound of FormulaI-8. The compound of Formula I-8 can then undergo the deprotection ofthe pinane ester and salicylic acid protective groups to afford thecompound of Formula Ia.

Synthesis of Prodrugs

Compounds of Formula I where the R is a prodrug moiety may besynthesized by a variety of known methods of different carboxylic acidprodrugs (Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed.,Springer, New York, 2007, which is incorporated herein by reference inits entirety). These prodrugs include but are not limited to substitutedor non-substituted alkyl esters, (acyloxy)alkyl esters (Synthesis 2012,44, 207, which is incorporated herein by reference in its entirety),[(alkoxycarbonyl)oxy]methyl esters (PCT Publication No. WO10097675,which is incorporated herein by reference in its entirety), or(oxodioxolyl)methyl esters (J. Med. Chem. 1996, 39, 323-338, which isincorporated herein by reference in its entirety). Such prodrugs can bemade from compounds of Formula I where R═H by treatment with acid or inneutral conditions (e.g., carbodiimide coupling) in the presence ofalcohols (ROH) or via base promoted esterification with RX where X is aleaving group in the presence of an appropriate base.

One exemplary but non-limiting general synthetic scheme for preparingthe prodrug is shown in Scheme 2a below. The boronic acid of Formula Iawhere R is hydrogen can react with a chloro/bromo-substituted prodrugmoiety to form a prodrug of Formula Ib. Examples of the prodrug moietyR^(Ib) can be —C₁₋₉alkyl, —CR¹R²OC(O)C₁₋₉alkyl, —CR¹R²OC(O)OC₁₋₉alkyl,and

Alternatively, compounds of Formula I may be also utilized forintroduction of prodrugs (Scheme 2b). Such carboxylic acids (VIII) canbe made from compounds of Formula Ia-1 by selective deprotection of OR′.The prodrug group may also be introduced earlier in the sequence incompounds of Formula Ia-4 or Ia-6 where R′ is R. Such a sequence wherethe prodrug is introduced in earlier intermediates is only feasible whenthe ester is stable under the final deprotection conditions to removethe phenol protective group and the boronate ester.

Administration and Pharmaceutical Compositions

The compounds are administered at a therapeutically effective dosage.While human dosage levels have yet to be optimized for the compoundsdescribed herein, generally, a daily dose may be from about 0.25 mg/kgto about 120 mg/kg or more of body weight, from about 0.5 mg/kg or lessto about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of bodyweight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus,for administration to a 70 kg person, the dosage range would be fromabout 17 mg per day to about 8000 mg per day, from about 35 mg per dayor less to about 7000 mg per day or more, from about 70 mg per day toabout 6000 mg per day, from about 100 mg per day to about 5000 mg perday, or from about 200 mg to about 3000 mg per day. The amount of activecompound administered will, of course, be dependent on the subject anddisease state being treated, the severity of the affliction, the mannerand schedule of administration and the judgment of the prescribingphysician.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indicationsthat are the subject of the preferred embodiments.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's The Science and Practice of Pharmacy, 21st Ed.,Lippincott Williams & Wilkins (2005), incorporated by reference in itsentirety. Accordingly, some embodiments include pharmaceuticalcompositions comprising: (a) a safe and therapeutically effective amountof a compound described herein (including enantiomers, diastereoisomers,tautomers, polymorphs, and solvates thereof), or pharmaceuticallyacceptable salts thereof; and (b) a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.

In addition to the selected compound useful as described above, comeembodiments include compositions containing apharmaceutically-acceptable carrier. The term “pharmaceuticallyacceptable carrier” or “pharmaceutically acceptable excipient” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. In addition, various adjuvantssuch as are commonly used in the art may be included. Considerations forthe inclusion of various components in pharmaceutical compositions aredescribed, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's:The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press,which is incorporated herein by reference in its entirety.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

The compositions described herein are preferably provided in unit dosageform. As used herein, a “unit dosage form” is a composition containingan amount of a compound that is suitable for administration to ananimal, preferably mammal subject, in a single dose, according to goodmedical practice. The preparation of a single or unit dosage formhowever, does not imply that the dosage form is administered once perday or once per course of therapy. Such dosage forms are contemplated tobe administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (e.g., from about 30minutes to about 2-6 hours), or administered as a continuous infusion,and may be given more than once during a course of therapy, though asingle administration is not specifically excluded. The skilled artisanwill recognize that the formulation does not specifically contemplatethe entire course of therapy and such decisions are left for thoseskilled in the art of treatment rather than formulation.

The compositions useful as described above may be in any of a variety ofsuitable forms for a variety of routes for administration, for example,for oral, nasal, rectal, topical (including transdermal), ocular,intracerebral, intracranial, intrathecal, intra-arterial, intravenous,intramuscular, or other parental routes of administration. The skilledartisan will appreciate that oral and nasal compositions comprisecompositions that are administered by inhalation, and made usingavailable methodologies. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. Pharmaceutically-acceptablecarriers include, for example, solid or liquid fillers, diluents,hydrotropies, surface-active agents, and encapsulating substances.Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical, and can be readily made by aperson skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid should be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations disclosed herein. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purifiedwater.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. For manycompositions, the pH will be between 4 and 9. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes,but is not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

For intravenous administration, the compounds and compositions describedherein may be dissolved or dispersed in a pharmaceutically acceptablediluent, such as a saline or dextrose solution. Suitable excipients maybe included to achieve the desired pH, including but not limited toNaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In variousembodiments, the pH of the final composition ranges from 2 to 8, orpreferably from 4 to 7. Antioxidant excipients may include sodiumbisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,thiourea, and EDTA. Other non-limiting examples of suitable excipientsfound in the final intravenous composition may include sodium orpotassium phosphates, citric acid, tartaric acid, gelatin, andcarbohydrates such as dextrose, mannitol, and dextran. Furtheracceptable excipients are described in Powell, et al., Compendium ofExcipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998,52 238-311 and Nema et al., Excipients and Their Role in ApprovedInjectable Products: Current Usage and Future Directions, PDA J PharmSci and Tech 2011, 65 287-332, both of which are incorporated herein byreference in their entirety. Antimicrobial agents may also be includedto achieve a bacteriostatic or fungistatic solution, including but notlimited to phenylmercuric nitrate, thimerosal, benzethonium chloride,benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided tocaregivers in the form of one more solids that are reconstituted with asuitable diluent such as sterile water, saline or dextrose in watershortly prior to administration. In other embodiments, the compositionsare provided in solution ready to administer parenterally. In stillother embodiments, the compositions are provided in a solution that isfurther diluted prior to administration. In embodiments that includeadministering a combination of a compound described herein and anotheragent, the combination may be provided to caregivers as a mixture, orthe caregivers may mix the two agents prior to administration, or thetwo agents may be administered separately.

The actual dose of the active compounds described herein depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan.

Some boronic acid derivatives described herein can form an oligomer suchas a dimer, trimer or tetramer. To prevent the boronic acid derivativesfrom forming such oligomers, some embodiments include pharmaceuticalcomposition in which an excipient is included that prevents or limitsthe formation of oligomers. The excipient can be a monosaccharide ormonosaccharide derivative. In one embodiment, the monosaccharide ormonosaccharide derivative is meglumine. Other excipients include but arenot limited to ethanolamine, diethanolamine,tris(hydroxymethyl)aminomethane (Tris), L-lysine, andPyridine-2-methanol.

Some embodiments described herein relate to a chemical complex formedbetween the monosaccharide or monosaccharide derivative and the compoundof Formula (III) described herein. In some embodiments, the interactionbetween the two components help increase the stability and/or solubilityof the compound of Formula (III).

More generally, in some embodiments the monosaccharide or monosaccharidederivative can form a chemical complex with any compound containing aboronate moiety. In some embodiments, the compound containing a boronatemoiety can be a boronic acid derivative described herein such as acompound of Formula (III) described herein. In other embodiments, thecompound containing a boronate moiety can be any other boronatecontaining compounds, for example, known boronate-containingpharmaceutical agents. In some other embodiments, the monosaccharide ormonosaccharide derivative used in forming the stable complex can bemeglumine.

In some embodiments, of the inclusion of meglumine in a pharmaceuticalcomposition prevents or reduces the formation of oligomers at a pH rangedesirable for pharmaceutical administration. In some embodiments, the pHof the composition can be in the range of about 5 to about 9, about 6 to8, about 6 to about 7.5, about 7.1 to about 7.3, or about 7.1 to about7.2. In some embodiments, the pH of the composition can be in the rangeof about 7.0-7.3. In some embodiments, the pH of the composition can beabout 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7,and 7.8. In some embodiments, the pH of the composition can be about7.1. In some embodiments, the pH of the composition can be about 7.2.

The amount of the boronic acid derivatives that are present in a monomerform can vary depending on the pH of the solution, theoligomer-preventing excipient included, and the amount of the excipientin the composition. In some embodiments, the percentage of the monomerform can be more than 85%, more than 88%, more than 90%, more than 92%,more than 95%, more than 97% by weight, based on the total amount of theboronic acid derivative in the composition. In some embodiments, thepercentage of the monomer form can be more than 96% by weight based onthe total amount of the boronic acid derivative in the composition. Insome embodiments, the percentage of the monomer form can be more than97% by weight based on the total amount of the boronic acid derivativein the composition.

Methods of Treatment

Some embodiments of the present invention include methods of treatingbacterial infections with the compounds and compositions comprising thecompounds described herein. Some methods include administering acompound, composition, pharmaceutical composition described herein to asubject in need thereof. In some embodiments, a subject can be ananimal, e.g., a mammal (including a human). In some embodiments, thebacterial infection comprises a bacteria described herein. As will beappreciated from the foregoing, methods of treating a bacterialinfection include methods for preventing bacterial infection in asubject at risk thereof.

In some embodiments, the subject is a human.

Further embodiments include administering a combination of compounds toa subject in need thereof. A combination can include a compound,composition, pharmaceutical composition described herein with anadditional medicament.

Some embodiments include co-administering a compound, composition,and/or pharmaceutical composition described herein, with an additionalmedicament. By “co-administration,” it is meant that the two or moreagents may be found in the patient's bloodstream at the same time,regardless of when or how they are actually administered. In oneembodiment, the agents are administered simultaneously. In one suchembodiment, administration in combination is accomplished by combiningthe agents in a single dosage form. In another embodiment, the agentsare administered sequentially. In one embodiment the agents areadministered through the same route, such as orally. In anotherembodiment, the agents are administered through different routes, suchas one being administered orally and another being administered i.v.

Examples of additional medicaments include an antibacterial agent,antifungal agent, an antiviral agent, an anti-inflammatory agent and ananti-allergic agent.

Preferred embodiments include combinations of a compound, composition orpharmaceutical composition described herein with an antibacterial agentsuch as a β-lactam. Examples of such β-lactams include Amoxicillin,Ampicillin (e.g., Pivampicillin, Hetacillin, Bacampicillin,Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin),Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin,Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin,Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g.,Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin,Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,Panipenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin,Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone,Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole,Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef,Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir,Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone,Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram,Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime,Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftiofur,Cefquinome, Cefovecin, Aztreonam, Tigemonam and Carumonam, CXA-101,RWJ-54428, MC-04,546, ME1036, RWJ-442831, RWJ-333441, or RWJ-333442.

Preferred embodiments include β-lactams such as Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem and Panipenem.

Additional preferred embodiments include β-lactams such as Aztreonam,Tigemonam, BAL30072, SYN 2416 and Carumonam.

Additional Examples of such β-lactams include penicillin, cephalosporin,carbapenem, monobactam, bridged monobactam, or combination thereof,wherein the penicillin is benzathine penicillin, benzylpenicillin,phenoxymethylpenicillin, procaine, penicillin, oxacillin, methicillin,dicloxacillin, flucloxacillin, temocillin, amoxicillin, ampicillin,co-amoxiclav, azlocillin, carbenicillin, ticarcillin, mezlocillin,piperacillin, apalcillin, hetacillin, bacampicillin, sulbenicillin,mecicilam, pevmecillinam, ciclacillin, talapicillin, aspoxicillin,cloxacillin, nafcillin, pivampicillin, or a combination thereof.

In some embodiments, the cephalosporin can be cephalothin, cephaloridin,cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine,ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin,cefoperazone, ceftizoxime, cefinenoxime, cefinetazole, cephaloglycin,cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide,cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam,cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoximeaxetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil,cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil,loracarbacef, latamoxef, or a combination thereof.

In some embodiments, the cephalosporin can be an anti-MRSAcephalosporin.

In some embodiments, the anti-MRSA cephalosporin is cefiobiprole,cefiaroline, or a combination thereof.

In some embodiments, the carbapenem is imipenem, meropenem, ertapenem,faropenem, doripenem, biapenem, panipenem, or a combination thereof.

In some embodiments, the carbapenem is an anti-MRSA carbapenem.

In some embodiments, the anti-MRSA carbapenem is PZ601 or ME1036.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises a monobactam. Examples ofmonobactams include aztreonam, tigemonam, nocardicin A, carumonam, andtabtoxin. In some such embodiments, the compound, composition and/orpharmaceutical composition comprises a class A, C, or D beta-lactamaseinhibitor. Some embodiments include co-administering the compound,composition or pharmaceutical composition described herein with one ormore additional agents.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises a class B beta lactamaseinhibitor. An example of a class B beta lactamase inhibitor includesME1071 (Yoshikazu Ishii et al, “In Vitro Potentiation of Carbapenemswith ME1071, a Novel Metallo-β-Lactamase Inhibitor, againstMetallo-β-lactamase Producing Pseudomonas aeruginosa Clinical Isolates.”Antimicrob. Agents Chemother. doi:10.1128/AAC.01397-09 (July 2010)).Some embodiments include co-administering the compound, composition orpharmaceutical composition described herein with one or more additionalagents.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises one or more agents thatinclude a class A, B, C, or D beta lactamase inhibitor. Some embodimentsinclude co-administering the compound, composition or pharmaceuticalcomposition described herein with the one or more additional agents.

Indications

The compounds and compositions comprising the compounds described hereincan be used to treat bacterial infections. Bacterial infections that canbe treated with the compounds, compositions and methods described hereincan comprise a wide spectrum of bacteria. Example organisms includegram-positive bacteria, gram-negative bacteria, aerobic and anaerobicbacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina,Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus,Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia,Haemophilus, Brucella and other organisms.

More examples of bacterial infections include Pseudomonas aeruginosa,Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonasalcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia,Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli,Citrobacter freundii, Salmonella typhimurium, Salmonella typhi,Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae,Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacteraerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratiamarcescens, Francisella tularensis, Morganella morganii, Proteusmirabilis, Proteus vulgaris, Providencia alcalifaciens, Providenciarettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobactercalcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,Bordetella pertussis, Bordetella parapertussis, Bordetellabronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilusducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamellacatarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacterjejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae,Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

The following examples will further describe the present invention, andare used for the purposes of illustration only, and should not beconsidered as limiting.

EXAMPLES Example 1(R)-2-hydroxy-3-(2-(trifluoromethylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (1)

Step 1: Synthesis of Compound 1B

To the mixture of TFAA (225 mL) and TFA (370 mL) was added compound 1A(45 g, 292 mmol) slowly at −10° C., followed by the addition of acetone(60 g, 1.03 mmol) in TFA (77 mL) over 1 h. After being stirred at −4° C.for 3 h, the solution was warmed up to room temperature and stirred for2 days before it was concentrated in vacuo to dryness. The residue wasdissolved in EtOAc, washed with NaHCO₃ solution, dried over Na₂SO₄.Column chromatography (hexanes/ethyl acetate/DCM, v/v/v, 20/1/20) gavethe titled compound 1B (28 g, 49.4% yield) as slightly yellow oil.

Step 2: Synthesis of Compound 1C

To the solution of compound 1B (28 g, 144.2 mmol) and triethylamine (73g, 721 mmol) in dichloromethane (300 mL) at −78° C. was added Tf₂O (81.3g, 288.4 mmol, 2 eq). The resulting mixture was warmed up to 0° C.slowly and stirred at 0° C. for 1 hour before it was quenched withwater. The mixture was extracted with DCM and dried over Na₂SO₄. Afterconcentrated to dryness, the residue was purified by columnchromatography (ethyl acetate/hexanes, v/v, 1/40) to give the titledcompound 1C (44 g, 93.6%) as a slightly yellow oil.

Step 3: Synthesis of Compound 1D

The mixture of compound 1C (21 g, 64.4 mmol), bis(pinacolato)diboron(21.3 g, 83.7 mmol), KOAc (18.9 g, 193 mmol) and PdCl₂(dppf) (2.6 g,3.22 mmol) in dioxane (200 mL) was degassed for three times and flushedwith nitrogen. The mixture was stirred at 95° C. for 15 hours. Afterconcentrated to dryness, the residue was purified by columnchromatography (ethyl acetate/hexanes, v/v, 1/100˜1/20) to give thetitled compound 1D (8.9 g, 45%) as slightly yellow oil.

Step 4: Synthesis of Compound 1E

Compound 1D (8.9 g, 29.3 mmol) was dissolved in THF (100 mL) and(+)-pinanediol (4.98 g, 29.3 mmol) was added. The resulting reactionmixture was stirred at room temperature for 15 hours. After concentratedto dryness, the residue was purified by column chromatography (ethylacetate/hexanes, v/v, 1/200˜1/50) to give the titled compound 1E (3.2 g,31% yield) as slightly yellow oil.

MS calcd for (C₂₀H₂₅BO₅): 356.

MS (ESI, positive) found: (M+1): 357.

Step 5: Synthesis of Compound 1F

To a solution of CH₂ICl (1.34 g, 7.67 mmol) in THF (15 mL) at −78° C.was added 2.5 M n-butyl lithium in hexane (3.07 mL, 7.67 mmol) slowlyunder nitrogen and down the inside wall of the flask. The resultingsolution was stirred for 30 minutes before the addition of Compound 1Efrom step 4 (2.1 g, 5.90 mmol) in THF (5 mL) at −78° C. The reaction wasallowed to warm to room temperature and stirred for 16 h before it wasquenched with a saturated solution of ammonium chloride. The phases wereseparated. The aqueous phase was extracted with diethyl ether (3×50 mL)and the combined organic extracts were dried over Na₂SO₄. Theconcentrated material was chromatographed (100% hexane-20% EtOAc-hexane)to obtain the titled compound 1F (2.07 g, 95% yield) as slightly yellowoil.

MS calcd for (C₂₁H₂₇BO₅): 370.

MS (ESI, positive) found: (M+1): 371.

Step 6: Synthesis of Compound 1G

To a solution of CH₂Cl₂ (0.72 mL, 11.2 mmol) in THF (20 mL) at −100° C.was added 2.5 M n-butyl lithium in hexane (2.9 mL, 7.28 mmol) slowlyunder nitrogen and down the inside wall of the flask, maintaining thetemperature below −90° C. The reaction mixture was stirred for 30minutes before the addition of Compound 1F from step 5 (2.07 g, 5.6mmol) in THF (5 mL) at −90° C. The reaction was allowed to warm to roomtemperature slowly and stirred at room temperature for 16 h. Thereaction mixture was quenched with a saturated solution of ammoniumchloride and the phases were separated. The aqueous phase was extractedwith diethyl ether (3×50 mL) and the combined organic extracts weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theconcentrated material was then chromatographed (100% hexane-20%EtOAc-hexane) to obtain the titled compound 1G (1.48 g, 63% yield) asslightly yellow oil.

Step 7: Synthesis of Compound 1H

Compound 1G (1.48 g, 3.53 mmol) in THF (15 mL) was cooled to −78° C.under nitrogen. A solution of 1 M LiHMDS solution in THF (3.6 mL, 3.6mmol) was added slowly at −78° C. Upon completion of the addition, thereaction flask was allowed to warm to room temperature. After stiffingat room temperature for 16 h, the reaction mixture was concentratedunder vacuum and hexane (20 mL) was added. The precipitated lithiumsalts were filtered off through a Celite pad, rinsed with additionalhexane and the combined filtrates were concentrated under vacuum to givecrude bis(trimethylsilyl)amine product 1H (3.5 mmol).

MS calcd for (C₂₈H₄₆BNO₅Si₂): 543.

MS (ESI, positive) found: (M−2*TMS+3): 400.

Step 8: Synthesis of Compound 1I

Bis(trimethylsilyl)amine compound 1H (260 mg, 0.48 mmol) was stirred inMeOH/THF (1 mL/10 mL) for 30 min at room temperature before it wasconcentrated to dryness in vacuo to afford the free amine as yellow oil.Trifluoromethylsulfanyl-acetic acid (91 mg, 0.57 mmol) and CDI (115 mg,0.71 mmol) were dissolved in DMF (2 mL) at stirred at 45° C. for 1 h.After cooling down, the free amine obtained above in 1 mL DMF was addedand was stirred at room temperature for 15 hours. The mixture wasdiluted with DCM and washed with water and brine, dried over Na₂SO₄. Theconcentrated material was then chromatographed (EtOAc-hexane: 1/20˜1/2)to obtain the titled compound 1I (110 mg, 42.5% yield) as slightlyyellow oil.

MS calcd for (C₂₅H₃₁BF₃NO₆S): 541.

MS (ESI, negative) found: (M−1): 540.

Step 9: Synthesis of(R)-2-hydroxy-3-(2-(trifluoromethylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (1)

To the solution of compound I (110 mg, 0.2 mmol) in MeOH/hexane (2 mL/2mL) was added isobutyl boronic acid (41 mg, 0.4 mmol) and concentratedHCl (0.2 mL) at 0° C. The resulting mixture was stirred at roomtemperature for 1 h. The two layers were separated and the MeOH layerwas washed with hexanes twice before it was concentrated in vacuo. Theresidue was stirred in dioxane (2 mL) and 3 N aqueous HCl (3 mL) at 80°C. for 2 h. After concentration, the residue was purified byreverse-phase prep-HPLC to afford 1 (8 mg) as a white solid afterlyophilization.

¹H NMR (400 MHz, CD₃OD) δ 7.83 (dd, 1H, J=6.0, 6.0 Hz), 7.32 (d, 1H,J=6.8 Hz), 6.96 (dd, 1H, J=8.0, 8.0 Hz), 3.86 (d, 2H, J=5.6 Hz), 3.34(s, 1H), 2.97 (s, 2H).

MS calcd for (C₁₂H₁₁BF₃NO₅S): 349.

MS (ESI, positive) found: (M+1): 350.

MS (ESI, negative) found: (M−1): 348.

Example 2(R)-2-hydroxy-3-(2-(1-methyl-1H-tetrazol-5-ylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (2)

Step 1: Synthesis of Compound 2A

Bis(trimethylsilyl)amine compound 1H (260 mg, 0.48 mmol) was stirred inMeOH/THF (1 mL/10 mL) for 1 h at room temperature before it wasconcentrated to dryness in vacuo to afford the free amine as yellow oil.(1-Methyl-1H-tetrazol-5-ylsulfanyl)-acetic acid (99 mg, 0.57 mmol) andCDI (115 mg, 0.71 mmol) were dissolved in DMF (2 mL) at stirred at 50°C. for 2 h. After cooling down, the free amine obtained above in 1 mLDMF was added and was stirred at room temperature for 15 hours. Themixture was diluted with DCM and washed with water and brine, dried overNa₂SO₄. After concentration, the crude compound 2A was used directly fornext step (205 mg, crude).

MS calcd for (C₂₆H₃₄BN₅O₆S): 555.

MS (ESI, negative) found: (M−1): 554.

Step 2: Synthesis of(R)-2-hydroxy-3-(2-(1-methyl-1H-tetrazol-5-ylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (2)

To the solution of compound 2A (200 mg, crude) in MeOH/hexane (1.5mL/1.5 mL) was added isobutyl boronic acid (82 mg, 0.8 mmol) andconcentrated HCl (0.15 mL) at 0° C. The resulting mixture was stirred atroom temperature for 1 h. The two layers were separated and the MeOHlayer was diluted with 10 mL MeOH, washed with hexanes twice before itwas concentrated in vacuo. The residue was stirred in dioxane (1.5 mL)and 3 N aqueous HCl (1.5 mL) at 80° C. for 2 h. After concentration, theresidue was purified by reverse-phase prep-HPLC to afford 2 (17 mg) as awhite solid after lyophilization.

¹H NMR (400 MHz, CD₃OD) δ 7.74 (dd, 1H, J=2.0, 8.4 Hz), 7.09 (d, 1H,J=6.4 Hz), 6.81 (t, 1H, J=7.6 Hz), 4.12-4.24 (m, 2H), 3.80 (s, 3H), 3.34(s, 1H), 2.89 (d, 2H, J=3.6 Hz).

MS calcd for (C₁₃H₁₄BN₅O₅S): 363.

MS (ESI, positive) found: (M+1): 364.

MS (ESI, negative) found: (M−1): 362.

Example 3(R)-3-(2-(difluoromethylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (3)

1C was prepared as described in example 1.

Step 1: Synthesis of Compound 3A

The mixture of compound 1C (10.8 g, 33.1 mmol), potassium vinyltrifluoroborate (5.3 g, 39.8 mmol), triethylamine (6.7 g, 9.3 mL, 66.2mmol) and PdCl₂(dppf) (1.35 g, 1.65 mmol) in i-PrOH (200 mL) wasdegassed for three times and flushed with nitrogen. The mixture wasstirred at 85° C. for 1 hour. After concentrated to dryness, the residuewas purified by column chromatography (ethyl acetate/hexanes, v/v,1/100˜1/40) to give the titled compound 3A (6.6 g, 98% yield) as aslightly yellow oil.

Step 2: Synthesis of Compound 3B

Benzoquinone (3.85 g, 35.6 mmol) and PdCl₂(CH₃CN)₂ (201 mg, 0.78 mmol)were added into t-BuOH (150 mL) at 85° C., followed by water (0.56 mL,31 mmol) and compound 3A (6.3 g, 31 mmol). The resulting solution wasstirred at 85° C. for 30 minutes until TLC indicating the disappearanceof compound 3A. After concentrated to dryness, the residue was purifiedby column chromatography (ethyl acetate/hexanes, v/v, 1/5˜1/2) to givethe titled compound 3B (4.1 g, 60% yield) as slightly yellow solid.

Step 3: Synthesis of Compound 3C

To a solution of compound 3B (2.0 g, 9.1 mmol) and(R)-tert-butylsulfinic amide (1.32 g, 10.9 mmol) in THF (40 mL) wasadded titanium(IV) ethoxide (3.8 mL, 18 mmol). The resulting solutionwas stirred at room temperature for 20 hours before it was quenched withbrine. The mixture was filtered through Celite and washed with EtOAc.The filtrate was concentrated and chromatographed (ethylacetate/hexanes, v/v, 1/21/1) to afford the titled compound 3C (2.04 g,70% yield) as slightly yellow solid.

Step 4: Synthesis of Compound 3E

The solution of compound 3C (1.9 g, 5.9 mmol), bis(pinacolato)diboron(1.7 g, 6.5 mmol) and NHC—Cu complex 3D (220 mg, 0.60 mmol) (For thesynthesis of compound 3D, see: J. Am. Chem. Soc. 2006, 128, 11036) inanhydrous benzene (20 mL) was stirred at room temperature under nitrogenatmosphere for 3 days. The reaction solution was diluted with EtOAc andwashed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄. Afterconcentration, the residue was quickly chromatographed (20%EtOAc-dichloromethane, silica gel was de-activated with 35 wt % water)to afford the titled compound 3E (2.6 g, quantitative yield) as yellowsolid.

Step 5: Synthesis of Compound 3F

To the solution of compound 3E (2.6 g, 5.9 mmol) in dioxane (30 mL) wasadded methanol (2.4 mL, 59 mmol) and HCl (1.6 mL, 6.5 mmol, 4M indioxane). The reaction mixture was concentrated to dryness in vacuo andwashed with ether/hexanes (v/v, 1/2). The residue (about 2.5 g) was usedfor next step without further purification.

Step 6: Synthesis of Compound 3H

Difluoromethylsulfanyl-acetic acid 3G (850 mg, 6.0 mmol) and CDI (1.01g, 6.3 mmol) were dissolved in DMF (15 mL) at stirred at 50° C. for 1 h.After cooling down, compound 3F in 12 mL DMF was added and the solutionwas stirred at room temperature for 4 hours. The mixture was dilutedwith hexanes/EtOAc (1/4, v/v) and washed with water (2×) and brine,dried over Na₂SO₄. After concentration, the crude compound 3H (1.8 g)was obtained as brown greasy solid, which was used directly for the nextstep.

Step 7: Synthesis of Compound 3I

The crude compound 3H (1.8 g, 3.8 mmol) and (+)-pinanediol (976 mg, 5.7mmol) were stirred in THF (20 mL) at room temperature for 16 hoursbefore it was concentrated to dryness. The residue was chromatographed(ethyl acetate/hexanes, v/v, 1/2˜1/1) to afford the titled compound 31(1.02 g) as orange oil.

MS calcd for (C₂₅H₃₂BF₂NO₆S): 523.

MS (ESI, negative) found: (M−1): 522.

Step 8: Synthesis of(R)-3-(2-(difluoromethylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (3)

To the solution of compound 31 (1.02 g, 1.95 mmol) in dioxane (50 mL)was added isobutyl boronic acid (800 mg, 7.8 mmol) and 3N aqueous HCl(20 mL). The resulting solution was stirred at 85° C. for 1.5 hours. Themixture was concentrated to about 20 mL and washed with hexanes and thenether. The organic layers were extracted with MeCN/water (v/v, 1/2). Thecombined water layer was purified by reverse-phase prep-HPLC to afford3, (283 mg) as a white solid after lyophilization.

¹H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 10.39 (s, 1H), 7.64 (d, 1H),7.34 (d, 1H), 7.01 (t, 1H), 6.80-6.96 (m, 1H), 3.60-3.82 (m, 2H),2.72-3.05 (m, 3H). MS calcd for (C₁₂H₁₂BF₂NO₅S): 331.

MS (ESI, positive) found: (M+1): 332.

MS (ESI, negative) found: (M−1): 330.

Example 4(R)-3-formamido-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (4)

3F was prepared as described in example 3.

Step 1: Synthesis of Compound 4A

To the solution of compound 3F (150 mg, 0.39 mmol) and formic acid (15mg, 0.32 mmol) in DCM/DMF (3 mL/1 mL) was added TEA (58 mg, 0.58 mmol)and diethyl cyanophosphonate (52 mg, 0.32 mmol). The resulting solutionwas stirred for 15 hours at room temperature before it was concentratedto dryness in vacuo. The residue was dissolved in THF and (+)-pinanediol(66 mg, 0.39 mmol) was added. After stiffing at room temperature for 3hours, the reaction mixture was concentrated and chromatographed (ethylacetate/hexanes, v/v, 1/2˜1/1) to afford the titled compound 4A (95 mg)as a yellow oil.

MS calcd for (C₂₃H₃₀BNO₆): 427.

MS (ESI, negative) found: (M−1): 426.

Step 2: Synthesis of(R)-3-formamido-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (4)

To the mixture of TFA (6 mL) and triethylsilane (1 mL) was addedcompound 4A (95 mg, 0.22 mmol). The resulting solution was stirred at50° C. for 1 hour before it was concentrated to dryness. The residue waswashed with Et₂O (20 mL), and purified by prep-HPLC to afford 4, 13.4mg) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.09 (s, 1H), 7.83 (d, 1H, J=8.0 Hz), 7.32 (d,1H, J=6.8 Hz), 6.97 (dd, 1H, J=7.2, 7.2 Hz), 3.22 (s, 1H), 2.97 (s, 2H).

MS calcd for (C₁₀H₁₀BNO₅): 235.

MS (ESI, positive) found: (M+1): 236.

MS (ESI, negative) found: (M−1): 234.

Example 5(R)-3-(2-(5-amino-1,3,4-thiadiazol-2-ylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (5)

3F was prepared as described in example 3.

Step 1: Synthesis of Compound 5A

To the solution of compound 3F (140 mg, 0.36 mmol) and(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-acetic acid (84 mg, 0.44 mmol)in DCM/DMF (3 mL/1 mL) was added TEA (81 mg, 0.80 mmol) and diethylcyanophosphonate (71 mg, 0.44 mmol). The resulting solution was stirredfor 3 hours at room temperature before it was concentrated to dryness invacuo. The residue was dissolved in THF and (+)-pinanediol (93 mg, 0.55mmol) was added. After stiffing at room temperature for 15 hours, thereaction mixture was concentrated and the residue was used directly fornext step.

MS calcd for (C₂₆H₃₃BN₄O₆S₂): 572.

MS (ESI, negative) found: (M−1): 571.

Step 2: Synthesis of(R)-3-(2-(5-amino-1,3,4-thiadiazol-2-ylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (5)

To the mixture of TFA (6 mL) and triethylsilane (1 mL) was added crudecompound 5A. The resulting solution was stirred at 50° C. for 1 hourbefore it was concentrated to dryness. The residue was washed with Et₂O(20 mL), and purified by prep-HPLC to afford 5 (35 mg) as white solid.

¹H NMR (400 MHz, CD₃OD) δ 7.79 (dd, 1H, J=1.6, 8.0 Hz), 7.25 (d, 1H,J=7.2 Hz), 6.94 (dd, 1H, J=8.0, 8.0 Hz), 3.90-4.06 (m, 2H), 3.31 (s,1H), 2.93 (s, 2H).

MS calcd for (C₁₃H₁₃BN₄O₅S₂): 380.

MS (ESI, positive) found: (M+1): 381.

MS (ESI, negative) found: (M−1): 379.

Example 6(R)-2-hydroxy-3-ureido-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (6)

3F was prepared as described in example 3.

Step 1: Synthesis of Compound 6A

To the solution of compound 3F (120 mg, 0.32 mmol) in DCM (3 mL) wasadded TMSNCO (43 mg, 0.38 mmol) and DIPEA (48 mg, 0.38 mmol). Theresulting solution was stirred for 2 hours at room temperature before itwas concentrated to dryness in vacuo. The residue was dissolved in THFand (+)-pinanediol (80 mg, 0.47 mmol) was added. After stiffing at roomtemperature for 15 hours, the reaction mixture was concentrated and theresidue was used directly for next step.

MS calcd for (C₂₁H₃₁BN₂O₆): 442.

MS (ESI, negative) found: (M−1): 441.

Step 2: Synthesis of(R)-2-hydroxy-3-ureido-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (6)

To the mixture of TFA (6 mL) and triethylsilane (1.5 mL) was added crudecompound 6A. The resulting solution was stirred at 50° C. for 1 hourbefore it was concentrated to dryness. The residue was washed with Et₂O(20 mL), and purified by prep-HPLC to afford 6 (5.2 mg) as white solid.

¹H NMR (400 MHz, CD₃OD) δ 7.81 (dd, 1H, J=2.0, 8.0 Hz), 7.30 (d, 1H,J=7.2 Hz), 6.94 (dd, 1H, J=7.6, 7.6 Hz), 3.18 (s, 1H), 2.84 (s, 2H).

MS calcd for (C₁₀H₁₁BN₂O₅): 250.

MS (ESI, positive) found: (M+1): 251.

MS (ESI, negative) found: (M−1): 249.

Example 7(R)-3-(2-(1,3,4-thiadiazol-2-ylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (7)

Step 1: Synthesis of Compound 7B

To the solution of compound 7A (100 g, 0.657 mol) in THF (400 mL) wasadded Boc₂O (573 g, 2.63 mol), DMAP (24 g, 0.197 mol) and t-BuOH (800mL). The resulting solution was stirred at 60° C. for 6 hours before itwas concentrated in vacuo. The residue was purified by flash columnchromatography (ethyl acetate/hexanes, v/v, 1/200˜1/100) to give thetitled compound 7B (85.9 g, 42.5% yield) as colorless oil.

Step 2: Synthesis of Compound 7C

To the solution of compound 7B (44.3 g, 144 mmol) and NBS (28.1 g, 158mmol) in CCl₄ (400 mL) was added BPO (3.5 g, 14.4 mmol). The resultingmixture was refluxed at 80° C. for 15 hours. The solid was filtered offand the filtrate was concentrated in vacuo. The residue wasrecrystallized with hexanes to afford the titled compound 7C (32.0 g,57.6% yield) as white solid.

Step 3: Synthesis of Compound 7D

The mixture of compound 7C (47.5 g, 123 mmol), bis(pinanediolato)diboron(39.9 g, 112 mmol), KOAc (32.9 g, 336 mmol) and PdCl₂(dppf) (4.5 g, 5.6mmol) in dioxane (500 mL) was degassed for three times and flushed withnitrogen. The mixture was stirred at 95° C. for 8 hours. Afterconcentrated to dryness, the residue was purified by columnchromatography (ethyl acetate/hexanes, v/v, 1/200˜1/100) to give thetitled compound 7D (40 g, 59% yield) as slightly yellow oil.

Step 4: Synthesis of Compound 7E

To a solution of CH₂Cl₂ (4.2 mL, 65.8 mmol) in THF (160 mL) at −100° C.was added 2.5 M n-butyl lithium in hexane (18.4 mL, 46.0 mmol) slowlyunder nitrogen and down the inside wall of the flask, maintaining thetemperature below −90° C. The reaction mixture was stirred at −100° C.for another 30 minutes before the addition of Compound 7D from step 3(16.0 g, 32.9 mmol) in THF (30 mL) at −90° C. and then the reaction wasallowed to warm to room temperature where it was stirred for 16 h. Thereaction was concentrated in vacuo directly to dryness and thenchromatographed (100% hexane-20% EtOAc-hexane) to obtain the titledcompound 7E (15.0 g, 85% yield) as slightly yellow oil.

Step 5: Synthesis of Compound 7F

Compound 7E (14.1 g, 26.4 mmol) in THF (100 mL) was cooled to −78° C.under nitrogen. A solution of LiHMDS (27 mL, 1.0M in THF, 27.0 mmol) wasadded slowly at −78° C. Upon completion of the addition, the reactionflask was allowed to warm to room temperature. After stiffing at roomtemperature for 2 h, the reaction mixture was concentrated under vacuumand hexane (100 mL) was added. The precipitated lithium salts werefiltered off through a Celite pad, rinsed with additional hexane, andthe combined filtrates were concentrated under vacuum to give crudebis(trimethylsilyl)amine product 7F (26.4 mmol), which was stored as astock solution for future use.

MS calcd for (C₃₄H₅₈BNO₇Si₂): 659.

MS (ESI, positive) found: (M−2*TMS+3): 516.

Step 6: Synthesis of Compound 7G

To the solution of ([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acid (655 mg,3.72 mmol) in DCM/DMF (10 mL/5 mL) was added HATU (1.40 g, 3.72 mmol) at0° C. After stirring at 0° C. for 15 minutes, a solution ofbis(trimethylsilyl)amine compound 7F (3.4 mmol) in DCM (5 mL) was added,followed by DIPEA (0.71 mL, 4.08 mmol). The resulting mixture was warmedup and stirred at room temperature for 1 hour, extracted with DCM (50mL*3), washed with water and brine, dried over Na₂SO₄. The concentratedmaterial was then chromatographed (EtOAc-hexane: v/v: 10/1-1/1) toobtain the titled compound 7G (1.35 g, 59% yield) as a slightly yellowgreasy solid.

MS calcd for (C₃₂H₄₄BN₃O₈S₂): 673.

MS (ESI, negative) found: (M+Na): 672.

Step 7: Synthesis of(R)-3-(2-(1,3,4-thiadiazol-2-ylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (7)

To the mixture of TFA (40 mL) and triethylsilane (6 mL) was addedcompound 7G (1.35 g, 2.01 mmol). The resulting solution was stirred atroom temperature for 1 hour before it was concentrated to dryness. Theresidue was washed with Et₂O (3×20 mL), and dissolved in CH₃CN/H₂O (20mL/20 mL), dried by lyophilization to afford 7 (380 mg, 52% yield) as awhite solid.

¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 7.73 (d, 1H, J=7.6 Hz), 7.15 (d,1H, J=7.2 Hz), 6.84 (dd, 1H, J=7.6, 7.6 Hz), 4.13-4.29 (m, 2H), 3.30 (s,1H), 2.91 (d, 2H, J=3.2 Hz).

MS calcd for (C₁₃H₁₂BN₃O₅S₂): 365.

MS (ESI, positive) found: (M+1): 366.

MS (ESI, negative) found: (M−1): 364.

Example 8(R)-3-(2-azidoacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (8)

7F was prepared as described in example 7.

Step 1: Synthesis of Compound 8B

To the solution of 2-azidoacetic acid (8A) (J. Med. Chem., 2011, 54,7375) (544 mg, 5.4 mmol) in DCM/DMF (20 mL/10 mL) was added HATU (2.05g, 5.4 mmol) at 0° C. After stirring at 0° C. for 15 minutes, a solutionof bis(trimethylsilyl)amine compound F (3.59 mmol) in DCM (10 mL) wasadded, followed by DIPEA (0.94 mL, 5.4 mmol). The resulting mixture waswarmed up and stirred at room temperature overnight, extracted with DCM(50 mL*3), washed with water and brine, dried over Na₂SO₄. Theconcentrated material was then chromatographed (EtOAc-hexane: v/v:10/1-1/1) to obtain the titled compound 8B (582 mg, 27% yield) as aslightly yellow greasy solid.

MS calcd for (C₃₀H₄₃BN₄O₈): 598.

MS (ESI, negative) found: (M−1): 597.

Step 2: Synthesis of(R)-3-(2-azidoacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (8)

To the mixture of TFA (46 mL) and triethylsilane (8 mL) was addedcompound 8B (582 mg, 0.97 mmol). The resulting solution was stirred atroom temperature for 1 hour before it was concentrated to dryness. Theresidue was partitioned in 20 mL water and 20 mL ether. The aqueouslayer was washed with ether (2×20 mL) and dried by lyophilization toafford (8, 120 mg, 43% yield) as white solid.

¹H NMR (400 MHz, CD₃OD) δ 7.83 (dd, 1H, J=2.0, 8.4 Hz), 7.31 (d, 1H,J=5.4 Hz), 6.97 (dd, 1H, J=7.6, 7.6 Hz), 4.25 (d, 2H, J=5.2 Hz), 3.31(s, 1H), 2.97 (d, 2H, J=3.2 Hz).

MS calcd for (C₁₁H₁₁BN₄O₅): 290.

MS (ESI, positive) found: (M+1): 291.

MS (ESI, negative) found: (M−1): 289.

Example 9(R)-3-(2-(dimethylamino)-2-oxoacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (9)

7F was prepared as described in example 7.

Step 1: Synthesis of 9B

To the solution of N,N-Dimethyl-oxalamic acid 9A (Heterocycles, 1993,36, 2687) (125 mg, 1.07 mmol) in DCM (3 mL) was added Ghosez reagent(157 mg, 1.18 mmol) at 0° C. After stiffing at 0° C. for 30 minutes, asolution of compound 7F in pyridine (1 mL) was added into the reactionmixture. The resulting mixture was stirred at room temperature for 3hours before it was concentrated to dryness. The residue was dissolvedin EtOAc, washed with water and brine, dried over Na₂SO₄. Afterconcentration, the crude 9B (157 mg) was obtained as yellow oil, whichwas used for next step without further purification.

MS calcd for (C₃₂H₄₇BN₂O₉): 614.

MS (ESI, negative) found: (M−1): 613.

Step 2: Synthesis of(R)-3-(2-(dimethylamino)-2-oxoacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (9)

To the mixture of 90% TFA (2 mL) and triethylsilane (0.5 mL) was addedcompound 9B (157 mg, crude). The resulting solution was stirred at roomtemperature for 1 hour before it was concentrated to dryness. Theresidue purified by reverse-phase prep-HPLC to afford 9, (5.4 mg) aswhite solid.

¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, 1H, J=7.6 Hz), 7.34 (d, 1H, J=6.8Hz), 6.98 (dd, 1H, J=7.6, 7.6 Hz), 3.37 (s, 1H), 2.85-3.05 (m, 2H), 2.88(s, 3H), 2.55 (s, 3H).

MS calcd for (C₁₃H₁₅BN₂O₆): 306.

MS (ESI, positive) found: (M+1): 307.

MS (ESI, negative) found: (M−1): 305.

Example 10(R)-3-(3-(dimethylamino)-3-oxopropanamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (10)

7F was prepared as described in example 7.

Step 1: Synthesis of 10B

Bis(trimethylsilyl)amine compound 7F (300 mg, 0.5 mmol) was stirred inMeOH/THF (1 mL/5 mL) for 30 min at room temperature before it wasconcentrated to dryness in vacuo to afford the free amine as a yellowoil. Compound 10A (WO 09117540) (76 mg, 0.58 mmol) and CDI (94 mg, 0.58mmol) were dissolved in DMF (2 mL) at stirred at 45° C. for 1 h. Aftercooling down, the free amine obtained above in 1 mL DMF was added andwas stirred at room temperature for 15 hours. The mixture was dilutedwith DCM and washed with water and brine, dried over Na₂SO₄. Afterconcentration, the crude titled compound 10B (345 mg) was obtained asslightly yellow oil, which was used for next step without furtherpurification.

MS calcd for (C₃₃H₄₉BN₂O₉): 628.

MS (ESI, negative) found: (M−1): 627.

Step 2: Synthesis of(R)-3-(3-(dimethylamino)-3-oxopropanamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (10)

To the mixture of 90% TFA (7 mL) and triethylsilane (2 mL) was addedcompound 10B (325 mg, crude). The resulting solution was stirred at roomtemperature for 1 hour before it was concentrated to dryness. Theresidue purified by reverse-phase prep-HPLC to afford 10 (40 mg) aswhite solid.

¹H NMR (400 MHz, CD₃OD) δ 7.83 (d, 1H, J=6.4 Hz), 7.32 (d, 1H, J=7.6Hz), 6.96 (dd, 1H, J=7.6, 7.6 Hz), 3.54-3.56 (m, 2H), 3.31 (s, 1H), 2.96(d, 2H, J=3.2 Hz), 2.82 (d, 6H, J=2.0 Hz).

MS calcd for (C₁₋₄H₁₇BN₂O₆): 320.

MS (ESI, positive) found: (M+1): 321.

MS (ESI, negative) found: (M−1): 319.

Example 11(R)-2-hydroxy-3-(methylthiocarbonylamino)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (11)

7F was prepared as described in example 7.

Step 1: Synthesis of 11A

Bis(trimethylsilyl)amine compound 7F (0.4 mmol) was stirred in MeOH/THF(0.5 mL/2 mL) for 30 min at room temperature before it was concentratedto dryness in vacuo to afford the free amine as a yellow oil. The freeamine was dissolved in DCM (2 mL) and pyridine (38 mg, 0.48 mmol) wasadded, followed by methyl chlorothiolformate (53 mg, 0.4 mmol). Afterstirring at room temperature for 12 hours, the reaction mixture wasdiluted with DCM, washed with water and brine, dried over Na₂SO₄. Afterconcentration, the crude titled compound 11A (280 mg) was obtained asyellow oil, which was used for next step without further purification.

MS calcd for (C₃₀H₄₄BNO₈S): 589.

MS (ESI, negative) found: (M−1): 588.

Step 2: Synthesis of(R)-2-hydroxy-3-(methylthiocarbonylamino)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (11)

To the mixture of TFA (2 mL) and triethylsilane (0.5 mL) was addedcompound C1 (280 mg, crude). The resulting solution was stirred at roomtemperature for 1 hour before it was concentrated to dryness. Theresidue purified by reverse-phase prep-HPLC to afford 11 (30 mg) aswhite solid.

¹H NMR (400 MHz, CD₃OD) δ 7.85 (dd, 1H, J=1.2, 8.0 Hz), 7.31 (d, 1H,J=7.6 Hz), 6.97 (dd, 1H, J=7.2, 8.0 Hz), 3.30 (s, 1H), 2.91 (s, 2H),2.39 (s, 3H).

MS calcd for (C₁₁H₁₂BNO₅S): 281.

MS (ESI, positive) found: (M+1): 282.

MS (ESI, negative) found: (M−1): 280.

Example 12(R)-2-hydroxy-3-(nicotinamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (12)

Intermediate 7F was made as described in example 7.

Step 1: Synthesis of 12A

To the solution of compound 7F (4 mmol, crude) and 3-pyridinecarboxylicacid (492 mg, 4 mmol) in DMF (40 mL) was added (EtO)₂POCN (652 mg, 4mmol). The resulting reaction mixture was stirred at room temperatureovernight before it was concentrated. The residue was dissolved in DCMand washed with water, brine and dried over Na₂SO₄. Columnchromatography gave titled compound 12A (1.311 g) as slightly yellowoil.

MS calcd for (C₃₄H₄₅BN₂O₈): 620.

MS (ESI, negative) found: (M−1): 619.

Step 2: Synthesis of(R)-2-hydroxy-3-(nicotinamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (12)

To the mixture of TFA (56 mL) and triethylsilane (16 mL) was addedcompound 12A (1.311 g). The resulting solution was stirred at roomtemperature for 1 hour before it was concentrated to dryness. Theresidue was washed with ether to afford 12 (450 mg) as white solid.

¹H NMR (400 MHz, CD₃OD) δ 9.18 (m, 1H), 8.98 (m, 1H), 8.42 (m, 1H), 7.98(m, 1H), 7.76 (m, 1H), 7.52 (m, 1H), 7.12 (m, 1H), 3.69 (s, 1H), 3.26(s, 2H).

MS calcd for (C₁₅H₁₃BN₂O₅): 312.

MS (ESI, positive) found: (M+1): 313.

MS (ESI, negative) found: (M−1): 311.

Example 13(R)-2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (13)

(R)-2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (13) was prepared following the procedure described in example 7(steps 1-7) replacing the ([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acidin step 6 with 2-(methylthio)acetic acid.

¹H NMR (400 MHz, CD₃OD) δ 7.84 (d, 1H, J=8.0 Hz), 7.33 (d, 1H, J=7.2Hz), 6.98 (d, 1H, J=7.6 Hz), 3.33 (S, 1H), 3.20 (s, 2H), 2.97 (s, 2H),1.70 (s, 3H).

MS calcd for (C₁₂H₁₄BNO₅S): 295.

MS (ESI, positive) found: (M+1): 296.

MS (ESI, negative) found: (M−1): 294.

Example 14(R)-3-(5-fluoronicotinamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (14)

(R)-3-(5-fluoronicotinamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (14) was prepared following the procedure described in example 7(steps 1-7) replacing the ([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acidin step 6 with 5-fluoronicotinic acid.

¹H NMR (400 MHz, CD₃OD) δ 11.10 (s, 1H), 8.84 (d, 2H, J=15.6 Hz), 8.10(d, 1H, J=8.8 Hz), 7.63 (d, 1H, J=7.2 Hz), 7.29 (d, 1H, J=6.8 Hz), 6.87(t, 1H, J=7.6 Hz), 3.25 (s, 1H), 2.95 (s, 2H).

MS calcd for (C₁₅H₁₂BFN₂O₅): 330.

MS (ESI, positive) found: (M+1): 331.

MS (ESI, negative) found: (M−1): 329.

Example 15(R)-2-hydroxy-3-(thiazole-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (15)

(R)-2-hydroxy-3-(thiazole-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (15) was prepared following the procedure described in example 7(steps 1-7) replacing the ([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acidin step 6 with thiazole-5-carboxylic acid.

¹H NMR (400 MHz, CD₃OD) δ 9.31 (s, 1H), 8.57 (s, 1H), 7.81 (d, 1H, J=8.0Hz), 7.33 (d, 1H, J=7.6 Hz), 6.94 (t, 1H, J=8.0 Hz), 3.48 (s, 1H), 3.05(s, 2H).

MS calcd for (C₁₅H₁₂BFN₂O₅): 318.

MS (ESI, positive) found: (M+1): 319.

MS (ESI, negative) found: (M−1): 317.

Example 16(R)-3-(3-amino-3-oxopropanamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (16)

Compound 16 above was prepared following the procedure described inExample 8 except replacing the 2-azidoacetic acid in step 1 with3-amino-3-oxopropanoic acid.

¹H NMR (400 MHz, CD₃OD) δ 7.82 (dd, 1H, J=1.2, 8.0 Hz), 7.31 (d, 1H,J=6.4 Hz), 6.94 (dd, 1H, J=7.2, 7.2 Hz), 3.27-3.32 (m, 3H), 2.95 (d, 2H,J=3.6 Hz).

MS calcd for (C₁₂H₁₃BN₂O₆): 292.

MS (ESI, positive) found: (M+1): 293.

MS (ESI, negative) found: (M−1): 291.

Example 17(R)-3-(2-amino-2-oxoacetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (17)

Compound (17) was prepared following the procedure described in example8 except replacing the 2-azidoacetic acid in step 1 with2-amino-2-oxoacetic acid.

¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, 1H, J=8.0 Hz), 7.31 (d, 1H, J=7.2Hz), 6.96 (dd, 1H, J=7.6, 7.6 Hz), 3.39 (t, 1H, J=4.0 Hz), 2.98 (d, 2H,J=3.6 Hz).

MS calcd for (C₁₁H₁₁BN₂O₆): 278.

MS (ESI, positive) found: (M-H2O+1): 261.

MS (ESI, negative) found: (M−1): 277.

Example 18(R)-2-hydroxy-3-(pyrimidine-5-carboxamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (18)

Compound (18) was prepared following the procedure described in Example8 except replacing the 2-azidoacetic acid in step 1 withpyrimidine-5-carboxylic acid.

¹H NMR (400 MHz, CD₃OD) δ 9.34 (s, 1H), 9.16 (s, 2H), 7.80 (d, 1H, J=6.8Hz), 7.34 (d, 1H, J=6.4 Hz), 6.94 (dd, 1H, J=7.6, 7.6 Hz), 3.51 (t, 1H,J=3.6 Hz), 3.09 (s, 2H).

MS calcd for (C_(m)H₁₂BN₃O₅): 313.

MS (ESI, positive) found: (M+1): 314.

MS (ESI, negative) found: (M−1): 312.

Example 19(R)-3-(5-amino-1,3,4-thiadiazole-2-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (19)

Compound (19) was prepared following the procedure described in example7 (steps 1-7) except replacing the([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acid in step 6 with5-(tert-butoxycarbonylamino)-1,3,4-thiadiazole-2-carboxylic acid.

5-(tert-butoxycarbonylamino)-1,3,4-thiadiazole-2-carboxylic acid wasprepared in accordance with the method described for preparing5-(tert-butoxycarbonylamino)-1,3,4-oxadiazole-2-carboxylic acid in PCTpublication WO 2010/144338, which is incorporated by reference in itsentirety.

¹H NMR (400 MHz, CD₃OD) δ 7.78 (dd, 1H, J=0.8, 8.0 Hz), 7.32 (d, 1H,J=6.8 Hz), 6.95 (dd, 1H, J=8.0, 8.0 Hz), 3.43 (t, 1H, J=3.6 Hz),3.01-3.04 (m, 2H).

MS calcd for (C₁₂H₁₁BN₄O₅S): 334.

MS (ESI, positive) found: (M+1): 335.

MS (ESI, negative) found: (M−1): 333.

Example 20(R)-3-(5-amino-1,3,4-oxadiazole-2-carboxamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (20)

Compound (20) was prepared following the same procedure described inexample 7 (steps 1-7) except replacing the([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acid in step 6 with5-(tert-butoxycarbonylamino)-1,3,4-oxadiazole-2-carboxylic acid inaccordance with the method described in PCT Publication WO 2010/144338,which is incorporated by reference in its entirety.

¹H NMR (400 MHz, CD₃OD) δ 7.81 (d, 1H), 7.32 (d, 1H), 6.95 (dd, 1H),3.44 (s, 1H), 3.03 (s, 2H).

MS calcd for (C₁₂H₁₁BN₄O₆): 318.

MS (ESI, negative) found: (M−1): 317.

Example 21(R)-2-hydroxy-3-(3-(methylamino)-3-oxopropanamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (21)

Compound (21) was prepared following the same procedure described inexample 7 (steps 1-7) except replacing the([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acid in step 6 with3-(methylamino)-3-oxopropanoic acid.

¹H NMR (400 MHz, CD₃OD) δ 7.82 (d, 1H), 7.30 (d, 1H), 6.96 (dd, 1H),3.30, (m, 1H), 3.27 (s, 2H), 2.96 (s, 2H), 2.63 (s, 3H).

MS calcd for (C₁₃H₁₅BN₂O₆): 306.

MS (ESI, positive) found: (M+1): 307.

MS (ESI, negative) found: (M−1): 305.

Example 22(R)-3-(2-(azetidin-3-ylthio)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylicacid (22)

Compound 22 was prepared following the same procedure described inexample 7 (steps 1-7) except replacing the([1,3,4]Thiadiazol-2-ylsulfanyl)-acetic acid in step 6 with2-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}sulfanyl)acetic acid.

¹H NMR (400 MHz, CD₃OD) δ 7.84 (d, 1H), 7.34 (d, 1H), 7.00 (dd, 1H),4.84 (m, 2H), 3.69-3.84 (m, 3H), 3.31-3.50 (m, 2H), 3.30 (m, 1H), 3.01(m, 2H).

MS calcd for (C_(m)H₁₇BN₂O₅S): 336.

MS (ESI, positive) found: (M+1): 337.

MS (ESI, negative) found: (M−1): 335.

General Procedure for Prodrug Formation:

To a solution of Compound 13 (0.5 mmol) in DMF (5 mL) was added a chloroor bromo substituted prodrug moiety (1 mmol), followed by K₂CO₃ (0.75mmol). The resulting mixture was stirred at 50° C. for 18 hours and thenbrought to room temperature. After the mixture was concentrated, theresidue was purified by prep-HPLC (C₁₈, acetonitrile and water as mobilephases, 0.1% formic acid) to obtain the titled compound. The followingcompounds were synthesized following this procedure.

Example 23 (R)-pivaloyloxymethyl2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylate(23)

¹H-NMR (400 MHz, CD₃OD) δ 7.55 (d, 1H), 7.21 (d, 1H), 6.82 (t, 1H), 5.93(m, 2H), 3.17 (s, 2H), 2.80-3.18 (m, 3H), 1.70 (s, 3H), 1.29 (d, 6H).

MS calcd for (C₁₈H₂₄BNO₇S) 409.

MS (ESI, negative) found: (M−1): 408.

Example 24 (R)-(isopropoxycarbonyloxy)methyl2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylate (24)

¹H-NMR (400 MHz, CD₃OD) δ 10.04 (bs, 1H), 7.59 (d, 1H), 7.22 (d, 1H),6.82 (t, 1H), 5.92 (m, 2H), 3.30 (m, 1H), 3.17 (s, 2H), 3.11 (m, 1H),2.82-2.89 (m, 2H), 1.69 (s, 3H), 1.21 (s, 9H).

MS calcd for (C₁₇H₂₂BNO₈S) 411.

MS (ESI, negative) found: (M−1): 410.

Example 25 (R)-butyryloxymethyl2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylate(25)

¹H-NMR (400 MHz, CD₃OD) δ 10.05 (bs, 1H), 7.57 (d, 1H), 7.21 (d, 1H),6.81 (t, 1H), 5.93 (m, 2H), 3.18 (s, 2H), 3.11 (m, 1H), 2.75-2.95 (m,2H), 2.37 (t, 2H), 1.62-1.70 (m, 5H), 0.90 (t, 3H).

MS calcd for (C₁₇H₂₂BNO₇S) 395.

MS (ESI, negative) found: (M−1): 394.

Example 26 (R)-(2-ethylbutanoyloxy)methyl2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylate(26)

¹H-NMR (400 MHz, CD₃OD) δ 7.57 (d, 1H), 7.21 (d, 1H), 6.82 (t, 1H), 5.96(s, 2H), 3.17 (s, 2H), 3.12 (s, 1H), 2.75-2.95 (m, 2H), 2.27 (m, 1H),1.69 (s, 3H), 1.48-1.70 (m, 4H), 0.90 (t, 6H).

MS calcd for (C₁₉H₂₆BNO₇S) 423.

MS (ESI, negative) found: (M−1): 422.

Example 27 (3R)-1-(ethoxycarbonyloxy)ethyl2-hydroxy-3-(2-(methylthio)acetamido)-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylate(27)

¹H-NMR (400 MHz, CD₃OD) δ 10.03 (bs, 1H), 7.56 (d, 1H), 7.20 (d, 1H),6.92, (m, 1H), 6.81 (t, 1H), 4.20 (q, 2H), 3.18 (s, 2H), 3.10 (s, 1H),2.75-2.90 (m, 2H), 1.70 (s, 3H), 1.58 (d, 3H), 1.28 (t, 3H).

MS calcd for (C₁₇H₂₂BNO₈S) 411.

MS (ESI, negative) found: (M−1): 410.

Example 28 Potentiation of Aztreonam

The potency and spectrum of β-lactamase inhibitors (BLIs) was determinedby assessing their aztreonam potentiation activity in a dose titrationpotentiation assay using strains of various bacteria that are resistantto aztreonam due to expression of various β-lactamases. Aztreonam is amonobactam antibiotic and is hydrolyzed by the majority ofbeta-lactamases that belong to class A or C (but not class B or D). Thepotentiation effect was observed as the ability of BLI compounds toinhibit growth in the presence of sub-inhibitory concentration ofaztreonam. MICs of test strains varied from 64 μg/mL to >128 μg/mL.Aztreonam was present in the test medium at 4 μg/mL. Compounds weretested at concentrations up to 40 μg/mL. In this assay potency ofcompounds was reported as the minimum concentration of BLI required toinhibit growth of bacteria in the presence of 4 μg/mL of aztreonam(MPC_(@4)). Table 1 summarizes the BLI potency of aztreonam potentiation(MPC_(@4)) for various strains overexpressing class A (ESBL and KPC),and class C beta-lactamases. Aztreonam MIC for each strain is alsoshown. The results were compared to comparative compounds A and B:

TABLE 1 Activity of BLIs to potentiate aztreonam against strainsexpressing class A and class C enzymes. Aztreonam MIC(μg/mL) >128 >128 >128 64 128 >128 64 >128 AZT AZT AZT AZT MPC4 MPC4MPC4 AZT MPC4 AZT AZT CTX-M- CTX- SHV- MPC4 TEM- MPC4 AZT MPC4 14 M-15 5SHV-12 10 KPC-2 MPC4 CMY-6 KP1005 KP1009 ec308 KP1010 ec302 KP1004ECL1002 EC1010 CPD A Y Y X X Y Y Y Y CPD B Z Z Y Y Z Z Z Z 2 X Y X X Y YY Y 1 Y Y X X Y Y Y Y 3 X Y X X Y Y Y X 4 Y Y Y X Y X Y X 8 X X X X Y XY X 5 X X X X Y Y Y X 6 Y Y Y Y Z X Z Y 7 X X X X Y Y Y X 9 Y Y X X Y YY Y 10 Y X Y X Y X Y X 11 Y Y X X Y Y Y Y 12 Y Y Y X X Y X Y 13 X X X XY X X X 14 Y Y Y X Y Y Y Y 15 Y Y X X X Y Y Y 16 X X X X X Y X X 17 Y YX X X Y Y Y 18 Y Y Y X X Y Y Y 19 Y Y X X Y Y Y X 20 Y X X X Y Y X X 21Y X X X Y Y X X 22 X X X X Y X X X X = MIC of less than 1 μg/mL Y = MICof 1 μg/mL to 10 μg/mL Z = MIC of greater than 10 μg/mL

Example 29 Potentiation of Tigemonam

Selected β-lactamase inhibitors were also tested for their ability topotentiate the monobactam tigemonam. The potentiation effect is observedas the ability of BLI compounds to inhibit growth in the presence ofsub-inhibitory concentration of tigemonam. MICs of test strains variedfrom 16 μg/mL to >64 μg/mL. Tigemonam was present in the test medium at4 μg/mL. Compounds were tested at concentrations up to 40 μg/mL. In thisassay potency of compounds was reported as the minimum concentration ofBLI required to inhibit growth of bacteria in the presence of 4 μg/mL ofaztreonam (MPC@₄). Table 2 summarizes the BLI potency of tigemonampotentiation (MPC_(@4)) for various strains overexpressing class A(ESBL) and class C beta-lactamases. Tigemonam MIC for each strain isalso shown. The results were compared to comparative compounds A and B:

TABLE 2 Activity of BLIs to potentiate tigemonam against strainsexpressing class A and class C enzymes. Tigemonam MIC(μg/mL) >64 >64 >64 >64 >64 32 16 TIG TIG TIG TIG TIG MPC₄ MPC₄ MPC₄MPC₄ MPC₄ TIG CTX- CTX- SHV- SHV- TEM- TIG MPC4 M-14 M-15 5 12 10 MPC4CMY-6 KP1005 KP1009 ec308 KP1010 ec302 ECL1002 EC1010 CPD A Y Y Y X Z YX CPD B Z Z Y Y Z Y Y 2 X Y X X Y X X 1 Y Y X X Z X X 3 X X X X Y Y X 4Y Y Y X Z X X 8 X X Y X Y X X 5 X X Y X Y X X 6 Z Y Z Y Z Y X 7 X X X XY Y X 9 Y Y Y Y Z Y Y 10 Y X Y X Z X X 11 Y Y Y X Z Y X 12 Y Y Y X Y X Y13 X X X X Y X X 14 Y Y Y X Y Y Y 15 Y Y Y X Y Y Y 16 Y X Y X Y X X 17 ZY Y Y X Y X 18 Y Y Y X Y Y X 19 Y Y X X Y Y X 20 Y X X X Y X X 21 Y Y YX Z X X 22 Y X Y X Z X X X = MIC of less than 1 μg/mL Y = MIC of 1 μg/mLto 10 μg/mL Z = MIC of greater than 10 μg/mL

Example 30 Potentiation of Biapenem

β-lactamase inhibitors were also tested for their ability to potentiatethe carbapenem biapenem against strains producing class A (KPC) andclass D (OXA-48) carbapenemases. The potentiation effect is observed asthe ability of BLI compounds to inhibit growth in the presence of asub-inhibitory concentration of biapenem. Biapenem MIC of test strainswere 16-32 μg/mL. Biapenem was present in the test medium at 1 μg/mL.Compounds were tested at concentrations up to 40 μg/mL. In this assaypotency of compounds was reported as the minimum concentration of BLIrequired to inhibit growth of bacteria in the presence of 1 μg/mL ofbiapenem (MPC_(@1)). Table 3 summarizes the BLI potency of biapenempotentiation (MPC_(@1)) for two strains overexpressing class A (KPC) andclass D (OXA-48) carbapenemases. Biapenem MIC for each strain is alsoshown. The results were compared to comparative compounds A and B:

TABLE 3 Activity of BLIs to potentiate biapenem against strainsexpressing class A (KPC) or class D (OXA-48) carbapenemases. BiapenemMIC (μg/mL) 32 16 BPM MPC₁ BPM MPC₁ KP1004 KPC-2 OXA-48 KP1086 CPD A X YCPD B X Z 2 X Y 1 X Y 3 X Y 4 X Y 8 X Y 5 X Y 6 X Y 7 X Y 9 X Z 10 X Y11 X Y 12 X Y 13 X Y 14 X Y 15 X Y 16 X Y 17 X Y 18 Y Y 19 X Y 20 X Y 21X Y 22 X Y X = MIC of less than 1 μg/mL Y = MIC of 1 μg/mL to 10 μg/mL Z= MIC of greater than 10 μg/mL

Example 31 Inhibitory Activity

K_(i) values of inhibition of purified class A, C and D enzymes weredetermined spectrophotometrically using nitrocefin as reportersubstrate. Purified enzymes were mixed with various concentrations ofinhibitors in reaction buffer and incubated for 10 min at roomtemperature. Nitrocefin was added and substrate cleavage profiles wererecorded at 490 nm every 10 sec for 10 min. The results of theseexperiments are presented in Table 5. These experiments confirmed thatthe described compounds are inhibitors with a broad-spectrum of activitytowards various β-lactamases. The results were compared to comparativecompounds A and B:

TABLE 4 Activity of BLIs (Ki, uM) to inhibit cleavage of nitrocefin bypurified class A, C and D enzymes Ki Ki Ki Ki (CTX- (SHV- (TEM- Ki Ki Ki(OXA- M-14, 12, 10, (KPC-2, (P99, (CMY-2, 48, NCF), NCF), NCF), NCF),NCF), NCF), NCF), uM uM uM uM uM uM uM CPD A X X Y Z Y X X CPD B X X Y ZY Y Y 2 Y X Y Y Y Y Y 1 Y X Y Y Y Y Y 3 Y X Y Z X Y X 4 Y Y Z Z Y Y Y 8Y X Y Z Y Y X 5 Y X X Z X X X 6 Y Y Z Z Z Z Z 7 X X Y Z X X Y 9 Y Y Y ZY Y Y 10 Y X Y Z Y Y Y 11 Y X Y Z X X X 12 X X Y Y X Y X 13 X Y Y Z Y YX 14 X X Y Z Y Y Y 15 X X Y Z Y Y X 16 Y X Z Z Y Y X 17 Y Y Z Z Y Y Y 18Y X Y Z Y Y Y 19 Y X Y Z Y ND Y 20 Y Y Y Z Y NF Y 21 Y X Y Z Y ND X 22 YX Y Z Y ND Y X = Less than 0.001 μM Y = 0.001 μM to 0.01 μM Z = Greaterthan 0.01 μM

Example 32 MexAB-OprM Dependent Efflux of BLIs

Efflux of BLIs from Pseudomonas aeruginosa by the MexAB-OprM efflux pumpwas also evaluated. The plasmid expressing the gene encoding KPC-2 wasintroduced into two strains of P. aeruginosa, PAM1032 and PAM1154 thatoverexpressed or lacked MexAB-OprM, respectively. Due to expression ofKPC-2 both strains became resistant to biapenem. Biapenem is notaffected by efflux in P. aeruginosa and both strains had the samebiapenem MIC of 32 μg/ml. Potency of BLIs to potentiate biapenem inthese strains was determined. Potency was defined as the ability of BLIto decrease MIC of biapenem 64-fold, from 32 μg/ml to 0.5 μg/ml, orMPC₆₄. The ratio of MPC₆₄ values for each BLI in PAM1032/KPC-2 (effluxproficient) and PAM1154/KPC-2 (efflux deficient) was determined togenerate the Efflux Index (EI). The results were compared to comparativecompound A:

Table 5 shows MPC₆₄ and EIs values for selected BLIs.

TABLE 5 MexAB-OprM Dependent Efflux of BLIs from P. aeruginosaPAM1032/KPC-2 PAM11154/KPC-2 Biapenem MPC₆₄ Biapenem MPC₆₄ EI CPD A 802.5 32 3 80 5 16 2 >80 10 >8 1 >80 5 >16 4 5 1.25 4 8 20 2.5 8 5 10 5 26 5 1.25 4 7 80 5 16 10 80 10 8 11 80 2.5 32 12 80 5 16 13 40 2.5 1614 >80 5 >16 15 80 2.5 32 16 20 5 4 17 80 5 16 18 ND ND ND 19 80 2.5 3220 80 10 8 21 40 10 4 22 2.5 2.5 1 X = Less than 10 Y = 10 to 40 ZGreater than 40

Example 33 Inhibition of Serine Proteases

The effect of selected BLIs on the enzymatic activity of some commonmammalian serine proteases was evaluated. Serine proteases used in thestudies are shown in Table 6.

TABLE 6 List of Serine Proteases Used to Evaluate Selectivity of BLIs.Catalog Enzyme Source number Trypsin Calbiochem 6502 ChymotrypsinCalbiochem 230832 Plasmin MPBio 19419890 Thrombin MPBio 19491880Elastase Calbiochem 324682 Urokinase Calbiochem 672112 Tissueplasminogen activator (TPA) Calbiochem 612220 Chymase Enzo LifescienceBML-SE281 Dipeptidyl peptidase 7 (DPP7) R&D Systems 3438-SE Dipeptidylpeptidase 8 (DPP8) BPS Bioscience 80080 Dipeptidyl peptidase 9 (DPP9)BPS Bioscience 80090 Neutrophil elastase Calbiochem 324681 CathepsinAR&D Systems 1049-SE CathepsinG EMD Millipore 219373

50 μl of the diluted enzyme was mixed with 50 μl of inhibitor at variousconcentrations and 50 μl of corresponding buffer (Table 7). Reactionmixtures were incubated for 10 min at 37° C. Subsequently, 50 μl ofcorresponding substrate (Table 7) was added and absorbance orfluorescence was monitored for 30 min on SpectraMax M2 plate reader(Molecular Devices). 4-(2-Aminoethyl) benzenesulfonyl fluoridehydrochloride (AEBSF) and leupeptin were used as positive controls.Rates of reaction were calculated and presented relative to “notreatment” control. IC50 values were calculated based on inhibitorconcentration producing 50% of enzyme inhibition. IC50 values forselected BLIs are shown in Tables 8A and 8B. The results were comparedto comparative compounds A and B:

TABLE 7 Enzyme substrates and buffers used in the study Substrate EnzymeBuffer Substrate conc, μM Trypsin 50 mM TrisHCl pH = 8.0, N-Bz-R-AMC 20010 mM CaCl2, 100 mM NaCl Chymotrypsin 20 mM TrisHCl pH = 8, Suc-AAPF-AMC10 150 mM NaCl, 2.5 mM CaCl2 Plasmin 100 mM TrisHCl pH = 7.5,H-D-VLK-pNA 200 100 mM NaCl Thrombin 20 mM TrisHCl pH = 8, Benz-FVR-AMC10 150 mM NaCl, 2.5 mM CaCl2 Elastase 25 mM Tris-HCl pH pH 8.0Suc-AAPA-pNA 50 Urokinase 50 mM Tris HCl, pH 8.5, NGK-pNA 100 38 mM NaClTissue 30 mM Tris-HCl, pH 8.5, GK-pNA 100 plasminogen 30 mM imidazole,130 mM NaCl activator (TPA) Chymase 100 mM Tris pH 8.0, 2M NaCl,Suc-AAPF-AMC 40 0.01% Triton X-100 Dipeptidyl 50 mM Na—Ac pH 5.8H-Lys-Pro-AMC 100 peptidase 7 (DPP7) Dipeptidyl 10 mM Tris pH 7.4, 10 mMMgCl2, Lys-Pro-AMC 100 peptidase 8 0.05% Tween-20 (DPP8) Dipeptidyl 25mM Tris pH 7.5, 0.1% BSA Lys-Pro-AMC 100 peptidase 9 (DPP9) Neutrophil50 mM TrisHCl pH = 7.5; MeOSuc-AAVP-AMC 30 elastase 1M NaCl CathepsinA25 mM MES, 5 mM DTT, pH 5.5 MCA-RPPGFSAFK-Dnp 10 CathepsinG 50 mM Na—Ac,pH 5.8, 2 mM EDTA, Suc-AAPF-AMC 100 1 mM DTT

TABLE 8A IC50 values (in μM) for serine proteases inhibition by selectedBLIs IC50, uM Compound Trypsin Chymotrypsin Thrombin Plasmin ElastaseUrokinase Chymase CPD A Z X X Z Z Z X CPD B ND Z Z ND ND ND Y 3 Z Z Z ZZ Z Y 4 Z Z Z Z Z Z Z 8 Z Z Z Z Z Z Z 5 Z Z Z Z Z Z Y 7 Z Z Z Z Z Z Z 11Z Z Z Z Z Z Z AEBSF 12.5 25 100 >200 222 8.2 375 Leupeptin <0.27 >200 155 >200 22 >200 X = IC50 of less than 300 μM Y = IC50 of 300 μM to 800 μMZ = IC50 of greater than 800 μM

TABLE 8B IC50 values (in μM) for serine proteases inhibition by selectedBLIs IC50, uM Neutrophil Cathepsin Compound elastase CathepsinA G HtrA2DPP7 DPP8 DPP9 CPD A Y X X Z Z Y Y CPD B Z Y Y ND ND Y Z 3 Y X X Z Z Z Z4 Z Z Y Z Z Z Z 8 Z Y X Z Z Z Z 5 Z Y X Z Z Y Z 7 Z Y Y ND Z Y Z 11 Z YY ND Z Z Z 12 ND Y X ND ND ND ND 14 ND Y Y ND ND ND ND 15 ND Y Y ND NDND ND AEBSF Z Y Z Z Z Z Z Leupeptin Y Y ND Z Y Y Y CathG ND ND X ND NDND ND inhibitor X = IC50 of less than 15 μM Y = IC50 of 15 μM to 500 μMZ = IC50 of greater than 500 μM

Example 34 Serum Stability of Prodrugs

Prodrug strategy is one of the ways to achieve or increase oralbioavailability of therapeutic drugs. Compound 13 was used as template afor various ester prodrugs. After a prodrug molecule is absorbed intosystemic circulation, the prodrug molecule can be hydrolyzed in theblood to release the active form. The hydrolysis of several prodrugs byrat and human serum were evaluated.

For all stability experiments the test compounds are treated with rat orhuman serum in Eppendorf tubes. One example of the testing proceduresincludes: 992 μl of serum was prewarmed at 37° C. for 2 minutes and then8 μl of a compound (at 5 mg/ml, 125×) was added to get a finalconcentration of 40 μg/ml and immediately mixed. Alternatively, serumstability can be tested at 1 mg/ml. The tube was placed back in a 37degree water bath and 100 μl-samples were taken at designated times andtransferred directly into Eppendorf tubes containing 400 μl ofprecipitant solution (a 4.00 μg/mL solution of a standard compound(2-((3R,6S)-3-benzamido-2-hydroxy-1,2-oxaborinan-6-yl)acetic acid)—in10% water, 45% methanol and 45% acetonitrile). After vortexing for 30seconds, the tube was centrifuged in a microcentrifuge for 10 minutes at15K rpm. Next, 100 μl of the supernatant was combined with 600 μl ofwater and injected on LC-MS using 0.1% formic acid in water for mobilephase A and 0.1% formic acid in methanol for mobile phase B on an ACE 5C18 2.1×100 mm column with a 10 μL injection. The flow rate and gradientare adjusted as needed to give the desired resolution and run time. ThepH of the mobile phase is adjusted if needed to improve thechromatography.

The time course of both the disappearance of a prodrug and theappearance of the active form of that prodrug is presented in Table 9aand Table 9b.

TABLE 9a The Time-course of hydrolysis of prodrugs by human serumMeasured Measured Initial Initial Conc. in Conc. at Conc. at Conc. inConc. at Conc. at Compound Serum t = 2 hr t = 4 hr Active Serum t = 2 hrt = 4 hr Name (ug/mL) (ug/mL) (ug/mL) Metabolite (ug/mL) (ug/mL) (ug/mL)23 1860 1350 1000 13 305 538 596 24 1790 550 240 13 214 900 1089 25 27.3NDT NDT 13 15 29.3 28.5 26 1520 920 790 13 220 415 583

TABLE 9b The Time-course of hydrolysis of prodrugs by rat serum MeasuredMeasured Initial Conc. Conc. at Conc. at Initial Conc. Conc. at Conc. atCompound in Serum t = 2 hr t = 4 hr Active in Serum t = 2 hr t = 4 hrName (ug/mL) (ug/mL) (ug/mL) Metabolite (ug/mL) (ug/mL) (ug/mL) 23 17801440 1100 13 286 428 486 24 1660 910 330 13 221 479 810 25 31.2 1.94 NDT13 13.8 27.6 27.6 26 1380 1150 1080 13 189 253 298 NDT signifies belowthe quantifiable limit for this assay.

Example 35 Formation of Salts/Complexes of Boronic Acid Derivatives toMaintain the Monomeric Form

The compounds described herein were observed to form oligomers (such asdimers and trimers) in aqueous solution. The effect of additives thatwould form a salt or complex with the boronic acid derivatives wasevaluated in order to identify those that would strongly favor themonomeric form at an acceptable pH for IV infusion (pH 4-8). A base orcomplexing agent was added to a dispersion of Compound 13 in water atthe given concentration (Table 10), and the formed mixture was sonicatedto provide a homogeneous solution. The pH of the resulting homogeneoussolution was measured with a pH meter and the purity was monitored byHPLC.

Several bases and complexing agents were screened to identify those thatwould afford the highest monomer content as salt/complex with a desiredpH. Oligomers were observed with one equivalent base or complexingagent. Oligomerization was more pronounced at higher concentrations withsome bases and complexing agents. Among all the bases screened, themeglumine complex gave the highest percentage of monomeric form at thedesired pH. A high percentage of monomeric form was observed atconcentrations up to 50 mg/mL while the pH remained close to 7.

The results of salt/complex formation are shown in Table 10. When theconcentration of Compound 13 was at 10 mg/m 1 and the pH of the solutionis at 7.1, about 97.3% of the Compound 13 in the solution was in amonomeric form. When the concentration of Compound 13 was at 50 mg/m 1and the pH of the solution is at 7.2, about 96.7% of the Compound 13 inthe solution was in a monomeric form.

TABLE 10 List of Salt/Complexes of Compound 13 and their Solution pH and% Purity of Monomer. Concentration Monomer of Compound Equivalentspurity by 13 (mg/mL) Salt/Complex of additive pH HPLC (%) 10 0.5N NaOH 17.3 51.3 10 0.5N NaOH 2 8.4 60.9 10 Ethanolamine 2 11 97.1 10Diethanolamine 2 11 92.2 10 Tris 2 7.8 94.7 50 Tris 2 7.7 89.7 50 Tris 38.5 95.4 3 L-Lysine 2 8.9 97.3 2 Pyridine-2-methanol 2 5.5 78 10Meglumine 2 7.1 97.3 50 Meglumine 2 7.2 96.7

Example 36 Intravenous Pharmacokinetics of Compounds

Rats (n=3 per compound) were administered by a single infusion. IV doseswere infused over 0.5 hours via an indwelling femoral vein cannula.Plasma (˜0.3 mL) samples were collected from each rat at designated timepoints up to 24 hours. Blood samples were centrifuged within 5 min ofcollection at 12000 g for 5 min to obtain plasma. The plasma sampleswere stored at −80° C. until analyzed. Data were analyzed usingWinNonlin.

TABLE 11 Intravenous Pharmacokinetics of select compounds Compound Dose(mg/kg) Free Cl (l/hr/kg) 3 20 2.45 4 20 1.73 8 10 2.10 5 20 1.71 7 203.64 12 10 2.74 13 20 2.47 16 10 0.87 19 10 1.25 22 20 0.57

Example 37 Oral Pharmacokinetics of Pro-Drugs of Compound 13

Rats (n=3 per compound) were administered a single oral dose. Oral doseswere administered as a bolus. Plasma (˜0.3 mL) samples were collectedfrom each rat at designated time points up to 24 hours. Blood sampleswere centrifuged within 5 min of collection at 12000 g for 5 min toobtain plasma. The plasma samples were stored at −80° C. until analyzed.Data were analyzed using WinNonlin.

TABLE 12 Bioavailability of Pro-Drugs of Compound 13 Dose of CompoundRange of % Oral Compound 13 from Pro-Drug (mg/kg) Bioavailability(Average) 23 36 15-26 (18.9) 25 15 19-36 (29.6) 26 45 18-34 (26.2) 27 3613-16 (14.2)

What is claimed is:
 1. A compound having the structure of Formula (I) orFormula (I.1):

or pharmaceutically acceptable salts thereof, wherein: G is selectedfrom the group consisting of —NR¹R², —CH₂N₃, —C(O)NR¹R², —CH₂C(O)NR¹R²,—CH₂S(O)₂NR¹R², —CH₂—Y—Z, —CH₂—Y—X, and —SR³; Y is selected from a groupconsisting of —S—, —S(O)—, —S(O)₂—, —O—, and —NR¹—; R is selected from agroup consisting of —H, —C₁₋₉ alkyl, —CR¹R²OC(O)C₁₋₉ alkyl,—CR¹R²OC(O)OC₁₋₉alkyl, and

R¹ and R² are each independently selected from the group consisting of—H and —C₁₋₄ alkyl; R³ is —C₁₋₄alkyl; R⁴ is present 1 to 3 times andeach R⁴ is independently selected from the group consisting of H,—C₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —S—C₁₋₄alkyl, halogen, and —CF₃, Z isselected from the group consisting of aryl optionally substituted withC₁₋₄alkyl, amino, hydroxy, or halogen; heteroaryl optionally substitutedwith C₁₋₄alkyl, amino, hydroxy, or halogen; and heterocycle optionallysubstituted with C₁₋₄alkyl, amino, hydroxy, or halogen; X is selectedfrom the group consisting of —C₁₋₄alkyl, —CH₂R⁵, —CH(R⁵)₂, and —C(R⁵)₃;and R⁵ is selected from the group consisting of a halogen, cyano, andazido.
 2. The compound of claim 1 having the structure of Formula (I):

or pharmaceutically acceptable salts thereof.
 3. The compound of claim1, wherein: each R⁴ is independently selected from the group consistingof —H, methyl, ethyl, propyl, iso-propyl, —OH, —O—C₁₋₄alkyl, andhalogen; and Z is selected from the group consisting of aryl optionallysubstituted with C₁₋₄alkyl, amino, hydroxy, or halogen and heteroaryloptionally substituted with C₁₋₄alkyl, amino, hydroxy, or halogen. 4.The compound of claim 1, having the structure of Formula (Ia) or Formula(Ia.1):

or pharmaceutically acceptable salts thereof.
 5. The compound of claim1, wherein R is H, CR¹R²OC(O)C₁₋₅alkyl, or —CR¹R²OC(O)OC₁₋₅alkyl,wherein R¹ in R is H and R² in R is H or —CH₃.
 6. The compound of claim1, wherein R⁴ is selected from H, F, Cl, —CH₃, —CF₃, —OCH₃, and —SCH₃.7. The compound of claim 1, wherein G is NH₂, C(O)NR¹R², orCH₂C(O)NR¹R², and wherein R¹ and R² in G are each independently selectedfrom —H and C₁₋₄alkyl.
 8. The compound of claim 7, wherein R¹ in G is—CH₃ and R² in G is H or —CH₃.
 9. The compound of claim 1, wherein: G is—CH₂—Y—Z; Y is —S—; and Z is selected from the group consisting ofimidazole, N-methylimidazole, aminoimidazole, triazole,N-methyltriazole, aminotriazole, tetrazole, N-methyltetrazole,aminotetrazole, thiazole, aminothiazole, thiadiazole, aminothiadiazole,oxazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine,azitidine and piperdine.
 10. The compound of claim 9, wherein Z isN-methyltetrazole, thiadiazole, aminothiadiazole, or azitidine.
 11. Thecompound of claim 1, wherein G is —SCH₃ or —CH₂—Y—X, wherein Y is —S—,and wherein X is —CH₃, —CH₂CN, —CH₂N₃, —CH₂F, —CHF₂, or —CF₃.
 12. Thecompound of claim 1, having the structure selected from the groupconsisting of:

or pharmaceutically acceptable salts thereof.
 13. A compound having thestructure of formula II or Formula II.1:

or pharmaceutically acceptable salts thereof, wherein: G is selectedfrom the group consisting of


14. The compound of claim 13 having the structure of Formula (II)

or pharmaceutically acceptable salts thereof.
 15. The compound of claim13, wherein G is selected from the group consisting of


16. The compound of claim 13, having the structure of Formula IIa orFormula IIa.1:

or pharmaceutically acceptable salts thereof.
 17. The compound of claim13, having the structure selected from the group consisting of:

or pharmaceutically acceptable salts thereof.
 18. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable excipient.
 19. Thepharmaceutical composition of claim 18, wherein the pharmaceuticallyacceptable excipient is meglumine.
 20. The pharmaceutical composition ofclaim 18, further comprising an additional medicament, and wherein theadditional medicament is selected from an antibacterial agent, anantifungal agent, an antiviral agent, an anti-inflammatory agent, or ananti-allergic agent.
 21. The composition of claim 20, wherein theadditional medicament is a β-lactam antibacterial agent, and wherein theβ-lactam antibacterial agent is selected from Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam,Tigemonam, BAL30072, SYN 2416, or Carumonam.
 22. A method oftherapeutically treating or preventing a bacterial infection, comprisingadministering to a subject in need thereof, a compound according toclaim 1, wherein the bacterial infection comprises a bacteria thatproduces a beta-lactamase.
 23. The method of claim 22, furthercomprising administering to the subject an additional medicament, andwherein the additional medicament is selected from an antibacterialagent, an antifungal agent, an antiviral agent, an anti-inflammatoryagent, or an anti-allergic agent.
 24. The method of claim 23, whereinthe additional medicament is a β-lactam antibacterial agent, and whereinthe β-lactam antibacterial agent is selected from Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam,Tigemonam, BAL30072, SYN 2416, or Carumonam.
 25. A pharmaceuticalcomposition, comprising: a monosaccharide or monosaccharide derivative,wherein the monosaccharide or monosaccharide, derivative is meglumine,and a compound of Formula (IIIa) or (IIIb):

or pharmaceutically acceptable salts thereof, wherein: J, L, and M areindependently CR⁴; R^(a) is selected from the group consisting of —H,halogen, optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionallysubstituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, optionally substituted—S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², —CN, optionally substituted—S(O)—C₁₋₆ alkyl, optionally substituted —S(O)₂—C₁₋₆ alkyl, —SO₃H,

R^(b) is selected from the group consisting of —H, halogen, optionallysubstituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionally substituted —O—C₁₋₆alkyl, —NR′R², and —N(OR³)R¹, optionally substituted —S—C₁₋₆ alkyl,—C(O)NR¹R², —S(O)₂NR′R², —CN, optionally substituted —S(O)—C₁₋₆ alkyl,optionally substituted —S(O)₂—C₁₋₆ alkyl, —SO₃H,

R^(c) is —OH; R^(d) is —OH; R^(e) is independently selected from thegroup consisting of hydrogen, optionally substituted C₁₋₆alkyl,optionally substituted C₃₋₇cycloalkyl, optionally substituted C₆₋₁₀aryl,optionally substituted 5-10 membered heteroaryl, and optionallysubstituted 3-10 membered heterocyclyl, or R^(d) and R^(e) together withthe nitrogen to which they are attached form a 5-8 membered heterocyclicring, optionally comprising additional 1-3 heteroatoms selected from 0,S or N; R^(f) is independently selected from the group consisting of —H,—OH, —C(O)G, —C(O)OG, —S(O)₂G, —C(═NR¹R²)G, —C(═NOR³)G, optionallysubstituted C₁₋₆ alkyl, optionally substituted —O—C₁₋₆alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,optionally substituted 5-10 membered heteroaryl, and optionallysubstituted 3-10 membered heterocyclyl; R^(g) and R^(h) are eachindependently selected from the group consisting of —H, C₁₋₆ alkyl, —OH,—OC₁₋₆alkyl, —SC₁₋₆alkyl, C₃₋₁₀cyclo alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl,—NR¹C(O)R⁵, —NR¹S(O)₂R³, —C(O)R⁵, —C(O)OR³-alkylaryl, optionallysubstituted C₆₋₁₀ aryl, optionally substituted —O—C₆₋₁₀aryl, —CN,optionally substituted 5-10 membered heteroaryl, optionally substituted—O-heteroaryl, optionally substituted 3-10 membered heterocyclyl,—S(O)(R³)R⁴, —S(O)₂R³, —R¹—O—COOR³, or R^(g) and R^(h) together with thecarbon to which they are attached form a C₃₋₈ cycloalkyl or a 4-8membered heterocyclyl; R is selected from the group consisting of —H,halogen, —C₁₋₉alkyl, —CR⁵R⁶OC(O)C₁₋₉alkyl, —CR⁵R⁶OC(O)OC₁₋₉alkyl, and

G is selected from the group consisting of hydrogen, —NR¹R², —CH₂N₃,—C(O)NR¹R², —CH₂C(O)NR¹R², —CH₂S(O)₂NR¹R², —(CH₂)_(n)—Y—Z,—(CH₂)_(n)—Y—X, —O—(CH₂)_(n)—C(O)NR¹R², —SR³, —CH₂NR¹C(O)R⁵,—C(═NOR³)—X, —C(═NOR³)—Z, —C(O)OR³, —C(O)—X, —C(O)—Z, —S(O)₂R³,—C(O)NR¹OR³, —NR¹(OR³), —NR¹C(O)R³, —NR¹C(O)NR²R^(1a), —NR¹C(O)OR³,—NR¹S(O)₂R³, —NR¹S(O)₂NR²R^(1a), —NR¹NR²R^(1a), —C(O)NR¹NR²R^(1a),—S(O)₂NR¹NR²R^(1a), —C(═NR¹)R⁵, —C(═NR¹)NR²R^(1a), —NR¹CR³(═NR²), and—NR¹C(═NR²)NR^(1a)R^(2a), optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 5-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; X is hydrogen or optionallysubstituted C₁₋₉alkyl; Y is selected from a group consisting of —S—,—S(O)—, —S(O)₂—, —CH₂—, —O—, —O—CH₂—, —C(O)—, and —NR¹—; Z is selectedfrom optionally substituted C₃₋₈ cycloalkyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted 5-10 membered heteroaryl; each R¹, R², R^(1a) and R^(2a) areindependently selected from the group consisting of —H, optionallysubstituted —C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted 3-8 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; R³ ishydrogen, optionally substituted C₁₋₁₀alkyl, —optionally substitutedC₁₋₁₀alkyl-COOH, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted 3-8 membered heterocyclyl, optionally substituted C₆₋₁₀aryl,and optionally substituted 5-10 membered heteroaryl; each R⁵ and R⁶areindependently selected from the group consisting of —H, —OH, —optionallysubstituted alkoxyl, optionally substituted —C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ cycloalkyl, optionally substituted 3-8membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R⁴ is present 1 to 5 times andeach R⁴ is independently selected from the group consisting of —H, —OH,halogen, —CF₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl,cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and—(CH₂)_(m)—Y′—(CH₂)_(p)M′; m and p are independently 0 to 3; Y′ isselected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR⁵R⁶—, and —NR¹—; M′ is selected from the group consisting of—C(O)NR¹R²; —C(O)NR¹OR³; —NR¹C(O)R⁵; —NR¹C(O)NR²R^(1a); —NR¹C(O)OR³;—NR¹S(O)₂R³; —NR¹S(O)₂NR²R^(1a); —C(═NR¹)R⁵; —C(═NR¹)NR²R^(1a);—NR¹CR⁵(═NR²); —NR¹C(═NR²)NR^(1a)R^(2a); C₁₋₄ alkyl optionallysubstituted with 0-2 substituents selected from the group consisting,—OR³, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; C₃₋₁₀ cycloalkyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, —OR³, —NR¹R², halogen, —C(O)NR¹R², and—NR¹C(O)R⁵; C₆₋₁₀ aryl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —OR³, —NR¹R², halogen,—C(O)NR¹R², and —NR¹C(O)R⁵; 5 to 10 membered heteroaryl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —OR³, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; and 4 to10 membered heterocyclyl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —OR³, —NR¹R², halogen,—C(O)NR¹R², and —NR¹C(O)R⁵; and each n is independently 0-3.
 26. Thecomposition of claim 25, wherein the compound of formula (IIIb) has thestructure of Formula (IIIc):

or pharmaceutically acceptable salts thereof.
 27. The composition ofclaim 25, wherein R^(a) is C(O)OR and R is H or —CR⁵R⁶OC(O)C₁₋₉ alkyl,and wherein each R⁵ and R⁶ is hydrogen.
 28. The composition of claim 25,wherein R^(e) is independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆alkyl, optionally substitutedC₃₋₇cycloalkyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, and optionally substituted 3-10 memberedheterocyclyl.
 29. The composition of claim 25, wherein R^(f) isindependently selected from the group consisting of —C(O)G, —C(O)OG, and—S(O)₂G.
 30. The composition of claim 25, wherein G is selected from thegroup consisting of


31. The composition of claim 25, wherein G is —NH₂, —NH—C₁₋₄ alkyl,—C(O)NR¹R², —CH₂C(O)NR¹R², or —O—(CH₂)_(n)—C(O)NR¹R², wherein n in G is0-3, and wherein R¹ and R² in G are each independently selected from —Hand C₁₋₄alkyl.
 32. The composition of claim 31, wherein G is—O—CH₂—C(O)NH₂.
 33. The composition of claim 25, wherein G is—(CH₂)_(n)—Y—Z; n in G is 0-3, Y is —S—; and Z is selected from thegroup consisting of imidazole, N-methylimidazole, aminoimidazole,triazole, N-methyl triazole, aminotriazole, tetrazole,N-methyltetrazole, aminotetrazole, thiazole, aminothiazole, thiadiazole,aminothiadiazole, oxazole, oxadiazole, pyridine, pyridazine, pyrimidine,pyrazine, azetidine and piperdine, each optionally substituted with oneor more C₁₋₄alkyl, —NR¹R², hydroxy, or halogen.
 34. The composition ofclaim 33, wherein Z is thiadiazole optionally substituted with one ormore C₁₋₄alkyl, —NR¹R², hydroxy, or halogen; aminothiadiazole optionallysubstituted with one or more C₁₋₄alkyl, —NR¹R², hydroxy, or halogen; orazitidine optionally substituted with one or more C₁₋₄alkyl, —NR¹R²,hydroxy, or halogen.
 35. The composition of claim 25, wherein G is—(CH₂)_(n)—Y—X; n in G is 0-3; Y is —S—; and X is hydrogen or optionallysubstituted C₁₋₄alkyl.
 36. The composition of claim 35, wherein X is—CH₃, —CH₂CN, —CH₂N₃, —CH₂F, —CHF₂, or —CF₃.
 37. The composition ofclaim 25, wherein G is —(CH₂)_(n)—Y—Z; n in G is 0-3, Y is —CH₂—, —O—,—O—CH₂—, —C(O)—; and Z is selected from the group consisting of phenyl,naphthyl, indole, pyrrolidine, thiophene, cyclopropyl, or cyclohexyl,each optionally substituted with one or more C₁₋₄alkyl, —NR¹R², hydroxy,or halogen.
 38. The composition of claim 25, wherein G is—(CH₂)_(n)—Y—X; n in G is 0-3; Y is —O— or —CH₂—; and X is C₁₋₄alkyloptionally substituted with one or more halogen, cyano, or azido.
 39. Apharmaceutical composition, comprising a monosaccharide ormonosaccharide derivative, wherein the monosaccharide or monosaccharide,derivative is meglumine, and a compound having the structure selectedfrom the group consisting of:

or pharmaceutically acceptable salts thereof.
 40. The composition ofclaim 25, wherein the pH of the composition is in the range of about 5to about
 9. 41. The composition of claim 40, wherein the pH of thecomposition is in the range of about 7.1 to about 7.3.
 42. Thecomposition of claim 25, further comprising an additionalpharmaceutically acceptable carrier or excipient.
 43. The composition ofclaim 25, further comprising one or more additional medicament, whereinthe additional medicament is selected from an antibacterial agent, anantifungal agent, an antiviral agent, an anti-inflammatory agent, or ananti-allergic agent.
 44. The composition of claim 43, wherein theadditional medicament is a β-lactam antibacterial agent, and wherein theβ-lactam antibacterial agent is selected from Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam,Tigemonam, BAL30072, SYN 2416, or Carumonam.
 45. A method oftherapeutically treating a bacterial infection, comprising administeringto a subject in need thereof, a composition according to claim 25,wherein the bacterial infection comprises a bacteria that produces abeta-lactamase.
 46. The method of claim 45, further comprisingadministering to the subject an additional medicament, and wherein theadditional medicament is selected from an antibacterial agent, anantifungal agent, an antiviral agent, an anti-inflammatory agent, or ananti-allergic agent.
 47. The method of claim 46, wherein the additionalmedicament is a β-lactam antibacterial agent, and wherein the β-lactamantibacterial agent is selected from Ceftazidime, Biapenem, Doripenem,Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam,BAL30072, SYN 2416, or Carumonam.
 48. A chemical complex, comprising acomplex between a monosaccharide or monosaccharide derivative, whereinthe monosaccharide or monosaccharide derivative is meglumine, and acompound having the structure of formula (IIIa) or (IIIb):

or pharmaceutically acceptable salts thereof, wherein: J, L, and M areindependently CR⁴; R^(a) is selected from the group consisting of —H,halogen, optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionallysubstituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R¹, optionally substituted—S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², —CN, optionally substituted—S(O)—C₁₋₆ alkyl, optionally substituted —S(O)₂—C₁₋₆ alkyl, SO₃H,

R^(b) is selected from the group consisting of —H, halogen, optionallysubstituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionally substituted —O—C₁₋₆alkyl, —NR¹R², and —N(OR³)R¹, optionally substituted —S—C₁₋₆ alkyl,—C(O)NR¹R², —S(O)₂NR¹R², —CN, optionally substituted —S(O)—C₁₋₆ alkyl,optionally substituted —S(O)₂—C₁₋₆ alkyl, SO₃H,

R^(c) is —OH; R^(d) is —OH; R^(e) is independently selected from thegroup consisting of hydrogen, optionally substituted C₁₋₆alkyl,optionally substituted C₃₋₇cycloalkyl, optionally substituted C₆₋₁₀aryl,optionally substituted 5-10 membered heteroaryl, and optionallysubstituted 3-10 membered heterocyclyl, or R^(d) and R^(e) together withthe nitrogen to which they are attached form a 5-8 membered heterocyclicring, optionally comprising additional 1-3 heteroatoms selected from O,S or N; R^(f) is independently selected from the group consisting of —H,—OH, —C(O)G, —C(O)OG, —S(O)₂G, —C(═NR¹R²)G, —C(═NOR³)G, optionallysubstituted C₁₋₆ alkyl, optionally substituted —O—C₁₋₆alkyl, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₆₋₁₀ aryl,optionally substituted 5-10 membered heteroaryl, and optionallysubstituted 3-10 membered heterocyclyl; R^(g) and R^(h) are eachindependently selected from the group consisting of —H, C₁₋₆ alkyl, —OH,—OC₁₋₆alkyl, —SC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl,—NR¹C(O)R⁵, —NR¹S(O)₂R³, —C(O)R⁵, —C(O)OR³-alkylaryl, optionallysubstituted C₆₋₁₀ aryl, optionally substituted —O—C₆₋₁₀aryl, —CN,optionally substituted 5-10 membered heteroaryl, optionally substituted—O-heteroaryl, optionally substituted 3-10 membered heterocyclyl,—S(O)(R³)R⁴, —S(O)₂R³, —R¹—O—COOR³, or R^(g) and R^(h) together with thecarbon to which they are attached form a C₃₋₈ cycloalkyl or a 4-8membered heterocyclyl; R is selected from the group consisting of —H,halogen, —C₁₋₉alkyl, —CR⁵R⁶OC(O)C₁₋₉alkyl, —CR⁵R⁶OC(O)OC₁₋₉alkyl, and

G is selected from the group consisting of hydrogen, —NR¹R², —CH₂N₃,—C(O)NR¹R², —CH₂C(O)NR¹R², —CH₂S(O)₂NR¹R², —(CH₂)_(n)—Y—Z,—(CH₂)_(n)—Y—X, —O—(CH₂)_(n)—C(O)NR¹R², —SR³, —CH₂NR¹C(O)R⁵,—C(═NOR³)—X, —C(═NOR³)—Z, —C(O)OR³, —C(O)—X, —C(O)—Z, —S(O)₂R³,—C(O)NR¹OR³, —NR¹(OR³), —NR¹C(O)R³, —NR¹NR²R^(1a), —C(O)NR¹NR²R^(1a),—S(O)₂NR¹NR²R^(1a), —C(═NR¹)R⁵, —C(═NR¹)NR²R^(1a), —NR¹CR³(═NR²), and—NR¹C(═NR²)NR^(1a)R^(2a), optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 5-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; X is hydrogen or optionallysubstituted C₁₋₉alkyl; Y is selected from a group consisting of —S—,—S(O)—, —S(O)₂—, —CH₂—, —O—, —O—CH₂—, —C(O)—, and —NR¹—; Z is selectedfrom optionally substituted C₃₋₈ cycloalkyl, optionally substituted 3-10membered heterocyclyl, optionally substituted C₆₋₁₀ aryl, optionallysubstituted 5-10 membered heteroaryl; each R¹, R², R^(1a) and R^(ea) areindependently selected from the group consisting of —H, optionallysubstituted —C₁₋₁₀alkyl, optionally substituted C₂₋₁₀alkenyl, optionallysubstituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted 3-8 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl; R³ ishydrogen, optionally substituted C₁₋₁₀alkyl, —optionally substitutedC₁₋₁₀alkyl-COOH, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted 3-8 membered heterocyclyl, optionally substituted C₆₋₁₀aryl,and optionally substituted 5-10 membered heteroaryl; each R⁵ and R⁶ areindependently selected from the group consisting of —H, —OH, —optionallysubstituted alkoxyl, optionally substituted —C₁₋₁₀alkyl, optionallysubstituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,optionally substituted C₃₋₇ cycloalkyl, optionally substituted 3-8membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R⁴ is present 1 to 5 times andeach R⁴ is independently selected from the group consisting of —H, —OH,halogen, —CF₃, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl,cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and—(CH₂)_(m)—Y′—(CH₂)_(p)M′; m and p are independently 0 to 3; Y′ isselected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR⁵R⁶—, and —NR¹—; M′ is selected from the group consisting of—C(O)NR¹R²; —C(O)NR¹OR³; —NR¹C(O)R⁵; —NR¹C(O)NR²R^(1a); —NR¹C(O)OR³;—NR¹S(O)₂R³; —NR¹S(O)₂NR²R^(1a); —C(═NR¹)R⁵; —C(═NR¹)NR²R^(1a);—NR¹CR⁵(═NR²); —NR¹C(═NR²)NR^(1a)R^(2a); C₁₋₄ alkyl optionallysubstituted with 0-2 substituents selected from the group consisting,—OR³, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; C₃₋₁₀ cycloalkyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, —OR³, —NR¹R², halogen, —C(O)NR¹R², and—NR¹C(O)R⁵; C₆₋₁₀ aryl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —OR³, —NR¹R², halogen,—C(O)NR¹R², and —NR¹C(O)R⁵; 5 to 10 membered heteroaryl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —OR³, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R⁵; and 4 to10 membered heterocyclyl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen,—C(O)NR¹R², and —NR¹C(O)R⁵; and each n is independently 0-3.